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Li X, Wei Y, Ruan Z, Wei G, Yao Z. Successful treatment of a keloid on the upper lip by trepanation and radiotherapy: a case report. J DERMATOL TREAT 2025; 36:2451394. [PMID: 39805259 DOI: 10.1080/09546634.2025.2451394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/11/2024] [Accepted: 12/24/2024] [Indexed: 01/16/2025]
Abstract
Purpose: Keloid tissue represents an abnormal proliferation of fibroblasts, typically resulting from skin injury. These lesions can lead to significant physiological dysfunction and aesthetic concerns, particularly when located on the face. Traditional treatments, such as intralesional injections, laser therapy, and surgical excision, have shown limited efficacy and are associated with high recurrence rates. Materials and methods: In a recent case, a 19-year-old male with a keloid on the upper lip did not respond to local injections of triamcinolone acetonide (TAC) or carbon dioxide ablative fractional resurfacing laser therapy. Results: A combined treatment approach involving trepanation and superficial radiotherapy successfully flattened the keloid tissue, with no recurrence observed during a 3-year follow-up period. Conclusions: This case underscores the potential efficiency and safety of combined therapeutic interventions and contributes valuable evidence towards the development of novel treatment strategies for keloids.
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Affiliation(s)
- Xianghui Li
- Department of Dermatology and Venereology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yong Wei
- Department of Dermatology and Venereology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhuren Ruan
- Department of Dermatology and Venereology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Gao Wei
- Department of Dermatology and Venereology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhijian Yao
- Department of Dermatology and Venereology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Sun Y, Qiao Y, Niu Y, Madhavan BK, Fang C, Hu J, Schuck K, Traub B, Friess H, Herr I, Michalski CW, Kong B. ARP2/3 complex affects myofibroblast differentiation and migration in pancreatic ductal adenocarcinoma. Int J Cancer 2025; 156:1272-1281. [PMID: 39472297 PMCID: PMC11737003 DOI: 10.1002/ijc.35246] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/23/2024] [Revised: 09/18/2024] [Accepted: 10/07/2024] [Indexed: 01/18/2025]
Abstract
The ARP2/3 complex, which orchestrates actin cytoskeleton organization and lamellipodia formation, has been implicated in the initiation of pancreatic ductal adenocarcinoma (PDAC). This study aims to clarify its impact on the activity of cancer-associated fibroblasts (CAFs), key players in PDAC progression, and patient outcomes. Early pancreatic carcinogenesis was modeled in p48Cre; LSL-KrasG12D mice with caerulein-induced pancreatitis, complemented by in vitro studies on human immortalized pancreatic stellate cells (PSCs) and primary PDAC-derived CAFs. Data were gained from microarray analysis, RNA sequencing (RNA-seq), and single-cell RNA sequencing (sc-RNA-seq), with subsequent bioinformatics analysis. We uncovered a specific transcriptional signature associated with fibroblast migration in early pancreatic carcinogenesis and linked it to poor survival in patients with PDAC. A pivotal role of the ARP2/3 complex in CAF migration was identified. Inhibition of the ARP2/3 complex markedly decreased CAF motility and induced significant morphological changes in vitro. Furthermore, its inhibition also hindered TGFβ1-mediated myofibroblastic CAF differentiation but had no effect on IL-1-mediated inflammatory CAF differentiation. Our findings position the ARP2/3 complex as central to the migration and differentiation of myofibroblastic CAF. Targeting this complex presents a promising new therapeutic avenue for PDAC treatment.
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Affiliation(s)
- Yifeng Sun
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
- Beijing Tsinghua Changgung Hospital, School of Clinical MedicineTsinghua UniversityBeijingChina
- Department of General and Visceral SurgeryUlm University HospitalUlmGermany
| | - Yina Qiao
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
| | - Yiqi Niu
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
- Department of General and Visceral SurgeryUlm University HospitalUlmGermany
| | | | - Chao Fang
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
- Department of General and Visceral SurgeryUlm University HospitalUlmGermany
| | - Jingxiong Hu
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
- Department of General and Visceral SurgeryUlm University HospitalUlmGermany
| | - Kathleen Schuck
- Department of General and Visceral SurgeryUlm University HospitalUlmGermany
| | - Benno Traub
- Department of General and Visceral SurgeryUlm University HospitalUlmGermany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, School of Medicine and HealthyTechnical University of Munich (TUM)MunichGermany
| | - Ingrid Herr
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
| | - Christoph W. Michalski
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
| | - Bo Kong
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
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Tu T, Hsu Y, Yang C, Shyong Y, Kuo C, Liu Y, Shih S, Lin C. Variations in ECM Topography, Fiber Alignment, Mechanical Stiffness, and Cellular Composition Between Ventral and Dorsal Ligamentum Flavum Layers: Insights Into Hypertrophy Pathogenesis. JOR Spine 2025; 8:e70033. [PMID: 39886656 PMCID: PMC11780719 DOI: 10.1002/jsp2.70033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/10/2024] [Revised: 10/22/2024] [Accepted: 12/03/2024] [Indexed: 02/01/2025] Open
Abstract
Background Previous studies have suggested that changes in the composition of the extracellular matrix (ECM) play a significant role in the development of ligamentum flavum hypertrophy (LFH) and the histological differences between the ventral and dorsal layers of the hypertrophied ligamentum flavum. Although LFH is associated with increased fibrosis in the dorsal layer, comprehensive research exploring the characteristics of the ECM and its mechanical properties in both regions is limited. Furthermore, the distribution of fibrosis-associated myofibroblasts within LFH remains poorly understood. This study aimed to bridge the existing knowledge gap concerning the intricate relationships between ECM characteristics, mechanical properties, and myofibroblast expression in LFH. Methods Histological staining, scanning electron microscopy, and atomic force microscopy were used to analyze the components, alignment, and mechanical properties of the ECM. Immunostaining and western blot analyses were performed to assess the distribution of myofibroblasts in LF tissues. Results There were notable differences between the dorsal and ventral layers of the hypertrophic ligamentum flavum. Specifically, the dorsal layer exhibited higher collagen content and disorganized fibrous alignment, resulting in reduced stiffness. Immunohistochemistry analysis revealed a significantly greater presence of α-smooth muscle actin (αSMA)-stained cells, a marker for myofibroblasts, in the dorsal layer. Conclusions This study offers comprehensive insights into LFH by elucidating the distinctive ECM characteristics, mechanical properties, and cellular composition disparities between the ventral and dorsal layers. These findings significantly enhance our understanding of the pathogenesis of LFH and may inform future research and therapeutic strategies.
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Affiliation(s)
- Ting‐Yuan Tu
- Department of Biomedical Engineering, College of EngineeringNational Cheng Kung UniversityTainanTaiwan
- Medical Device Innovation CenterNational Cheng Kung UniversityTainanTaiwan
- International Center for Wound Repair and RegenerationNational Cheng Kung UniversityTainanTaiwan
| | - Yu‐Chia Hsu
- Department of Orthopedic Surgery, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
| | - Chia‐En Yang
- Department of Biomedical Engineering, College of EngineeringNational Cheng Kung UniversityTainanTaiwan
| | - Yan‐Jye Shyong
- Department of Clinical Pharmacy and Pharmaceutical SciencesNational Cheng Kung UniversityTainanTaiwan
| | - Cheng‐Hsiang Kuo
- International Center for Wound Repair and RegenerationNational Cheng Kung UniversityTainanTaiwan
- Department of Biochemistry and Molecular Biology, College of MedicineNational Cheng Kung UniversityTainanTaiwan
| | - Yuan‐Fu Liu
- Department of Orthopedic Surgery, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
| | - Shu‐Shien Shih
- Medical Device Innovation CenterNational Cheng Kung UniversityTainanTaiwan
| | - Cheng‐Li Lin
- Medical Device Innovation CenterNational Cheng Kung UniversityTainanTaiwan
- Department of Orthopedic Surgery, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
- Musculoskeletal Research Center, Innovation HeadquartersNational Cheng Kung UniversityTainanTaiwan
- Skeleton Materials and Bio‐Compatibility Core Lab, Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
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Yin S, Shi P, Han J, Li H, Ren A, Ma L, Tang W, Liu W, Yu S, Li T, Wang C, Hou Y, Zhang J. Pathological and molecular insights into intravenous leiomyomatosis: an integrative multi-omics study. J Transl Med 2025; 23:229. [PMID: 40011937 DOI: 10.1186/s12967-024-05919-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/03/2024] [Accepted: 11/25/2024] [Indexed: 02/28/2025] Open
Abstract
Intravenous leiomyomatosis (IVL) is a histologically well differentiated smooth muscle tumor with aggressive behavior, capable of extending throughout the venous system. Understanding how IVL occurs and develops is really important for diagnosing and treating it. Unfortunately, because IVL is quite rare, there aren't many comprehensive studies available. In our research, we carried out an extensive multi-omics study, gathering tissue samples from IVL cases, uterine fibroid, and normal myometrium. The single-cell RNA sequencing analysis revealed a notable difference in cell composition between IVL and uterine fibroid. Additionally, H&E staining demonstrated more frequent hydropic changes and hyalinization in IVL tissues, along with a reduced vascular density compared to both normal myometrium and uterine fibroid. In our proteomics analysis of eight paired samples of IVL and normal myometrium fresh frozen tissue, we identified proteins that were differentially expressed, mainly related to focal adhesions and regulation of the actin cytoskeleton. The most frequently involved chromosomes included deletions in 10q22.2, 10q24.32, 13q14, and 13q21-31. Correlation analyses highlighted chromosome 10q as the most frequent cytoband, with corresponding proteins involved in regulating focal adhesions and the cytoskeleton. Integrated analysis between pathological and clinical characteristics indicated that chromosome 10q deletion and vascular morphology in IVL could serve as important markers predicting aggressive behavior. Our study sheds light on the pathological and molecular changes linked to IVL, which could pave the way for new treatment approaches.
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Affiliation(s)
- Sheng Yin
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Peipei Shi
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Han
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hua Li
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Aimin Ren
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Ma
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenbin Tang
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenxue Liu
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sihui Yu
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tingting Li
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chunsheng Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jiarong Zhang
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Fudan University, Shanghai, China.
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5
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Min S, Kim KM, Park JH, Lee M, Hwang J, Park JU. Novel therapeutic strategy for intractable keloids: suppression of intracellular mechanotransduction and actin polymerization via Rho-kinase pathway inhibition. Br J Dermatol 2025; 192:458-467. [PMID: 39392935 DOI: 10.1093/bjd/ljae384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/16/2024] [Revised: 09/06/2024] [Accepted: 09/18/2024] [Indexed: 10/13/2024]
Abstract
BACKGROUND Keloid is a dermal fibrotic disorder characterized by excessive extracellular matrix production by fibroblasts. Despite the significance of mechanostimulation in fibrotic diseases, its association with keloid pathophysiology or treatment remains unexplored. OBJECTIVES To investigate the role of mechanical force in keloid formation and elucidate the significance of Rho-associated coiled-coil-containing kinase 1 (ROCK1) as a mechanoresponsive target for keloid treatment. METHODS Patient-derived keloid fibroblasts (KFs) were subjected to cyclic stretching ranging from 0% to 20% elongation using a cell-stretching system. We observed the inhibitory effects of the ROCK1 inhibitor Y27632 on KFs and keloid formation. Validation was performed using a keloid xenograft severe combined immune-deficient (SCID) mouse model. RESULTS ROCK1 was overexpressed in KFs isolated from patients. Cyclic stretching induced fibroblast proliferation and actin polymerization by activating Rho/ROCK1 signalling. Treatment with Y27632 downregulated fibrotic markers reduced the migration capacity of KFs and induced extensive actin cytoskeleton remodelling. In the keloid xenograft SCID mouse model, Y27632 effectively suppressed keloid formation, mitigating inflammation and fibrosis. CONCLUSIONS The ROCK1 inhibitor Y27632 is a promising molecule for keloid treatment, exerting its effects through actin cytoskeleton remodelling and nuclear inhibition of fibrotic markers in keloid pathogenesis.
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Affiliation(s)
- Sally Min
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Ki-Myo Kim
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jun Ho Park
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Mihyun Lee
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Joseph Hwang
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Ji-Ung Park
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
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Auguet-Lara M, Skrivergaard S, Therkildsen M, Rasmussen MK, Young JF. Development of a biomarker panel for cell characterization intended for cultivated meat. Exp Cell Res 2025; 446:114467. [PMID: 39978714 DOI: 10.1016/j.yexcr.2025.114467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/20/2024] [Revised: 02/14/2025] [Accepted: 02/16/2025] [Indexed: 02/22/2025]
Abstract
Cultivated meat has in recent years been suggested as a sustainable alternative to produce meat at large-scale. Several aspects of cultivated meat production have demonstrated significant progress. However, there are still many questions regarding the cell culture, media composition, and the production itself to be answered and optimized. Finding good starter cell populations is a challenge to address and requires robust tools to characterize the cell populations. Detailed analysis is required to identify each type of cell within the skeletal muscle niche leads to optimized cultivated meat production at large-scale. In this study, we developed a set of biomarkers, using digital droplet PCR (ddPCR) and Immunofluorescence (IF) staining, to identify specific cell types within a heterogeneous cell population isolated from skeletal muscle tissue. We showed that combining Neural Cell Adhesion Molecule (NCAM), Calponin 1 (CNN1), and Fibronectin (FN), can be a powerful approach to predict the growth of skeletal myotubes, smooth muscle mesenchymal cells (SMMCs), and myofibroblasts, respectively. Moreover, early cell-cell interactions of fibroblastic cells were observed to be triggered through thin actin filaments containing CNN1 protein, to form, subsequently, myofibroblast networks. Besides, Myogenic Differentiation 1 (MyoD) is the key marker to detect skeletal muscle growth, whereas Myogenic Factor 5 (MyF5) can be expressed in myogenic and non-myogenic cells. MyF5 was detected at differentiation stages within the myotube nuclei, suggesting an unknown role during myotube formation.
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Alekseeva LA, Sen'kova AV, Sounbuli K, Savin IA, Zenkova MA, Mironova NL. Pulmozyme Ameliorates LPS-Induced Lung Fibrosis but Provokes Residual Inflammation by Modulating Cell-Free DNA Composition and Controlling Neutrophil Phenotype. Biomolecules 2025; 15:298. [PMID: 40001601 DOI: 10.3390/biom15020298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/26/2024] [Revised: 01/28/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Pulmonary fibrosis, a chronic progressive lung disorder, can be the result of previous acute inflammation-associated lung injury and involves a wide variety of inflammatory cells, causing the deposition of extracellular matrix (ECM) components in the lungs. Such lung injury is often associated with excessive neutrophil function and the formation of DNA networks in the lungs, which are also some of the most important factors for fibrosis development. Acute lung injury with subsequent fibrosis was initiated in C57Bl/6 mice by a single intranasal (i.n.) administration of LPS. Starting from day 14, human recombinant DNase I in the form of Pulmozyme for topical administration was instilled i.n. twice a week at a dose of 50 U/mouse. Cell-free DNA (cfDNA), DNase activity, and cell content were analyzed in blood serum and bronchoalveolar lavage fluid (BALF). Inflammatory and fibrotic changes in lung tissue were evaluated by histological analysis. The gene expression profile in spleen-derived neutrophils was analyzed by RT-qPCR. We demonstrated that Pulmozyme significantly reduced connective tissue expansion in the lungs. However, despite the reliable antifibrotic effect, complete resolution of inflammation in the respiratory system of mice treated with Pulmozyme was not achieved, possibly due to enhanced granulocyte recruitment and changes in the nuclear/mitochondrial cfDNA balance in the BALF. Moreover, Pulmozyme introduction caused the enrichment of the spleen-derived neutrophil population by those with an unusual phenotype, combining pro-inflammatory and anti-inflammatory features, which can also maintain lung inflammation. Pulmozyme can be considered a promising drug for lung fibrosis management; however, the therapy may be accompanied by residual inflammation.
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Affiliation(s)
- Ludmila A Alekseeva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Lavrentiev Ave., 8, Novosibirsk 630090, Russia
| | - Aleksandra V Sen'kova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Lavrentiev Ave., 8, Novosibirsk 630090, Russia
| | - Khetam Sounbuli
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Lavrentiev Ave., 8, Novosibirsk 630090, Russia
- Faculty of Natural Sciences, Novosibirsk State University, Pirogova St., 1, Novosibirsk 630090, Russia
| | - Innokenty A Savin
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Lavrentiev Ave., 8, Novosibirsk 630090, Russia
| | - Marina A Zenkova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Lavrentiev Ave., 8, Novosibirsk 630090, Russia
| | - Nadezhda L Mironova
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (SB RAS), Lavrentiev Ave., 8, Novosibirsk 630090, Russia
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Castro C, Patin J, Jajkiewicz C, Chizelle F, Cerpa CO, Tessier A, Le Pogam E, Fellah I, Baró I, Charpentier F, Derangeon M. Long QT syndrome type 3 gain-of-function of Na v1.5 increases ventricular fibroblasts proliferation and pro-fibrotic factors. Commun Biol 2025; 8:216. [PMID: 39934335 DOI: 10.1038/s42003-025-07636-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/05/2023] [Accepted: 01/30/2025] [Indexed: 02/13/2025] Open
Abstract
The long QT syndrome type 3 (LQT3) is a cardiac channelopathy caused by gain-of-function mutations in the SCN5A gene, encoding the sodium channel Nav1.5. As Nav1.5 is expressed in cardiomyocytes but also in cardiac fibroblasts, we investigated whether the LQT3-causing p.ΔQKP1507-1509 (ΔQKP) SCN5A mutation alters cardiac fibroblast phenotype. Primary cultured ventricular fibroblasts from Scn5a+/ΔQKP knock-in mice showed increased proliferation, survival, expression of transforming growth factor-β (TGF-β) and activation of its canonical pathway, and reduced α-smooth muscle actin expression. Ventricular tissue from Scn5a+/ΔQKP mice exhibited augmented fibroblast populations and fibrosis. Inhibiting TGF-β receptor, sodium current or Scn5a expression decreased Scn5a+/ΔQKP fibroblast proliferation, while veratridine increased proliferation of control fibroblasts, mimicking Nav1.5 gain-of-function. Lastly, abnormal calcium signaling underlied the increased proliferation of Scn5a+/ΔQKP fibroblasts. Our study shows that cardiac fibroblasts carrying the ΔQKP-SCN5A mutation exhibit an abnormal, proliferative phenotype, paving the way for better understanding the role of cardiac fibroblasts in LQT3.
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Affiliation(s)
- Claire Castro
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
- Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Justine Patin
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Cyrielle Jajkiewicz
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Franck Chizelle
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Cynthia Ore Cerpa
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Agnès Tessier
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Eva Le Pogam
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Imen Fellah
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Isabelle Baró
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Flavien Charpentier
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France
| | - Mickaël Derangeon
- Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.
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9
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Kang M, Ko UH, Oh EJ, Kim HM, Chung HY, Shin JH. Tension-sensitive HOX gene expression in fibroblasts for differential scar formation. J Transl Med 2025; 23:168. [PMID: 39930512 PMCID: PMC11808978 DOI: 10.1186/s12967-025-06191-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/01/2024] [Accepted: 01/31/2025] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Scar formation is a common end-point of the wound healing process, but its mechanisms, particularly in relation to abnormal scars such as hypertrophic scars and keloids, remain not fully understood. This study unveils a novel mechanistic insight into scar formation by examining the differential expression of Homeobox (HOX) genes in response to mechanical forces in fibroblasts derived from normal skin, hypertrophic scars, and keloids. METHODS We isolated fibroblasts from different scar types and conducted RNA sequencing (RNA-Seq) to identify differential gene expression patterns among the fibroblasts. Computational modeling provided insight into tension alterations following injury, and these findings were complemented by in vitro experiments where fibroblasts were subjected to exogenous tensile stress to investigate the link between mechanical tension and cellular behavior. RESULTS Our study revealed differential HOX gene expression among fibroblasts derived from normal skin, hypertrophic scars, and keloids. Computational simulations predicted injury-induced tension reduction in the skin, and in vitro experiments revealed a negative correlation between tension and fibroblast proliferation. Importantly, we discovered that applying mechanical tension to fibroblasts can modulate HOX gene expression, suggesting a pivotal role of mechanical cues in scar formation and wound healing. CONCLUSION This study proposes a model wherein successful wound healing and scar formation are critically dependent on maintaining tensional homeostasis in the skin, mediated by tension-sensitive HOX genes. Our findings highlight the potential of targeting mechanotransduction pathways and tension-sensitive HOX gene expression as therapeutic strategies for abnormal scar prevention and treatment, offering a new perspective on the complex process of scar formation.
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Affiliation(s)
- Minwoo Kang
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Ung Hyun Ko
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Eun Jung Oh
- Department of Plastic & Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Hyun Mi Kim
- Department of Plastic & Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Ho Yun Chung
- Department of Plastic & Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Jennifer H Shin
- Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
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10
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Gao C, Jian C, Wang L, Liu Y, Xiong Y, Wu T, Shi C. FAP-targeting biomimetic nanosystem to restore the activated cancer-associated fibroblasts to quiescent state for breast cancer radiotherapy. Int J Pharm 2025; 670:125190. [PMID: 39788396 DOI: 10.1016/j.ijpharm.2025.125190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/22/2024] [Revised: 12/07/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
Cancer associated fibroblasts (CAFs) are one of the most important stromal cells in the tumor microenvironment, playing a pivotal role in the development, recurrence, metastasis, and immunosuppression of cancer and treatment resistance. Here, we developed a core-shell biomimetic nanosystem termed as FAP-C NPs. This system was comprised of 4T1 extracellular vesicles fused with a FAP single-chain antibody fragment to form the biomimetic shell, and PLGA nanoparticles loaded with calcipotriol as the core. The FAP-modified shell endowed this nanosystem with active targeting ability to CAFs. Calcipotriol, a vitamin D analog, can activate the vitamin D receptor expressed on CAFs, promoting their transition from an activated to quiescent state. This process would help to reduce the pro-tumorigenic signals generated by CAFs, inhibit the stemness of cancer cells, and attenuate the inhibitory effect of CAFs on immune cells. The hydrated particle size of FAP-C NPs was approximately 206 nm, with a narrow distribution (polydispersity index < 0.2). The zeta potential of FAP-C NPs was -12.63 ± 0.61 mV. FAP-C NPs can restore CAFs to a quiescent state to shield the function of activated CAFs, inhibit tumor cell stemness, facilitate the maturation of dendritic cell, and relieve the inhibition of CAFs on lymphocytes. Besides, when combined with radiotherapy, this biomimetic nanosystem could inhibit the activation of CAFs, improve the sensitivity to radiation, and stimulate potent anti-tumor immune response with a 2-fold increase in the infiltration of cytotoxic T cells in tumor microenvironment, thereby effectively suppressing tumor growth with the tumor inhibitory rate as 78.3 %. Therefore, FAP-C NPs hold great potential for targeted breast cancer therapy.
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Affiliation(s)
- Chen Gao
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Chen Jian
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Lulu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Yajing Liu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Yiquan Xiong
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Tingting Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China.
| | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China.
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11
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Zhang T, Hou Z, Ding Z, Wang P, Pan X, Li X. Single Cell RNA-Seq Identifies Cell Subpopulations Contributing to Idiopathic Pulmonary Fibrosis in Humans. J Cell Mol Med 2025; 29:e70402. [PMID: 39928535 PMCID: PMC11809556 DOI: 10.1111/jcmm.70402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/31/2024] [Revised: 01/15/2025] [Accepted: 01/21/2025] [Indexed: 02/12/2025] Open
Abstract
The cell populations, particularly subpopulations, involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) remain incompletely understood. This study employed single-cell RNA-seq to identify cell populations and subpopulations with significantly altered proportions in the lungs of patients with IPF. In IPF lungs, endothelial cell proportions were significantly increased, while alveolar epithelial cell proportions were markedly decreased. Among the three identified fibroblast subpopulations, the proportion of myofibroblasts was significantly increased, while the proportions of the other two fibroblast subtypes were reduced. Similarly, within the three macrophage subpopulations, the macrophage_SPP1 subpopulation, localised to fibroblastic foci, showed a significant increase in proportion, while the alveolar macrophage subpopulation was significantly reduced. Trajectory analysis revealed that fibroblasts in IPF lungs could differentiate into myofibroblasts, and alveolar macrophages could transition into the macrophage_SPP1 subpopulation. Among T-cell subpopulations, only the CD4 T_FOXP3 subpopulation exhibited a significant change, whereas all four B-cell subpopulations showed significant proportional shifts. These findings provide a comprehensive view of the cellular alterations contributing to IPF pathogenesis. Extensive interactions among various cell populations and subpopulations were identified. The proportions of various cell populations and subpopulations in IPF lungs, including endothelial cells, fibroblasts, macrophages and B cells, were significantly altered. Further in-depth investigation into the roles of cell subpopulations with significantly altered proportions in the onset and progression of IPF will provide valuable insights into the pathological mechanisms underlying the disease. This understanding could facilitate the development of novel therapeutic strategies and medications for IPF treatment.
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Affiliation(s)
- Tangjuan Zhang
- Department of EmergencyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zhichao Hou
- Department of Thoracic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Zheng Ding
- Department of Thoracic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Peng Wang
- School of Nursing and HealthZhengzhou UniversityZhengzhouChina
| | - Xue Pan
- School of Nursing and HealthZhengzhou UniversityZhengzhouChina
| | - Xiangnan Li
- Department of Thoracic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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12
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Panda B, Chilvery S, Devi P, Kalmegh R, Godugu C. Inhibition of peptidyl arginine deiminase-4 ameliorated pulmonary fibrosis via modulating M1/M2 polarisation of macrophages. Life Sci 2025; 362:123354. [PMID: 39755270 DOI: 10.1016/j.lfs.2024.123354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/26/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/06/2025]
Abstract
Pulmonary fibrosis (PF) arises from dysregulated wound healing, leading to excessive extracellular matrix (ECM) deposition and impaired lung function. Macrophages exhibit high plasticity, polarizing to pro-inflammatory M1 during early inflammation and anti-inflammatory, fibrosis-inducing M2 during later stages of PF. Additionally, neutrophils and neutrophil extracellular traps (NETs) release mediated by peptidyl arginine deiminase (PAD-4), also play a key role in PF progression. PAD-4 inhibitor chloro-amidine (CLA) has shown anti-fibrotic effects in bleomycin (BLM) induced PF mouse model in our earlier study. Here, we have demonstrated that CLA also exhibited inhibition of macrophage polarisation in in-vitro in THP-1 monocytes and in-vivo in BLM induced PF. THP-1 monocytes were exposed to NETs isolated from phorbol 12-myristate-13-acetate (PMA) stimulated and PMA plus CLA treated differentiated HL-60 (dHL-60) cells. Monocytes exposed to stimulated NETs resulted in increased oxidative stress, disrupted mitochondrial membrane potential and increased M1 and M2 macrophage markers. These alterations were abrogated in THP-1 cells upon exposure to CLA treated NETs. Further, CLA treatment in BLM induced mice improved abnormal BALF, biochemical, and histological parameters in line with our previous findings. Additionally, CLA also reduced M1 and M2 markers time-dependently, as shown by immunofluorescence (IF), western blot, and RT-PCR analysis. CLA treatment led to decreased expression of PAD-4, M1-related pro-inflammatory cytokines and M2-related pro-fibrotic cytokines and mediators, as confirmed by western blot and ELISA analysis. Thus, it is established that inhibition of PAD-4 lead to mitigation of macrophage polarisation and a combined anti-fibrotic effect is achieved which can be explored further.
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Affiliation(s)
- Biswajit Panda
- Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, TS 500037, India
| | - Shrilekha Chilvery
- Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, TS 500037, India
| | - Priyanka Devi
- Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, TS 500037, India
| | - Radha Kalmegh
- Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, TS 500037, India
| | - Chandraiah Godugu
- Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, TS 500037, India.
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13
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Peng X, Li G, Zhao J, Liu H, Wu C, Su Z, Liu Z, Fan S, Chen Y, Wu Y, Liu W, Shen H, Zheng G. Promotion of quiescence and maintenance of function of mesenchymal stem cells on substrates with surface potential. Bioelectrochemistry 2025; 164:108920. [PMID: 39904300 DOI: 10.1016/j.bioelechem.2025.108920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/16/2024] [Revised: 01/20/2025] [Accepted: 01/26/2025] [Indexed: 02/06/2025]
Abstract
The widespread use of human mesenchymal stem cells(hMSCs) is impeded by functional loss during prolonged expansion. Although multiple approaches have been attempted to preserve hMSCs stemness, a suitable culture system remains to be modified. The interaction between electrical signals and stem cells is expected to better maintain the function of stem cells. However, it remains unclear whether the surface potential of substrates has the potential to preserve stem cell function during in vitro expansion. In our study, hMSCs cultured on materials with different surface potentials could be induced into a reversible quiescent state, and we demonstrated that quiescent hMSCs could be reactivated and transitioned back into the proliferation cell cycle. hMSCs cultured under appropriate potential displayed superior differentiation and proliferation abilities within the same generation compared to conventional conditions. These findings underscore the importance of surface potential as a critical physical factor regulating hMSCs stemness. Manipulating the surface potential of hMSCs culture substrates holds promise for optimising preservation and culture conditions, thereby enhancing their application in tissue repair and regeneration engineering.
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Affiliation(s)
- Xiaoshuai Peng
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Guojian Li
- Department of Spine Orthopedics, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai 519000, PR China
| | - Jiu Zhao
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Huatao Liu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Changhua Wu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Zepeng Su
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Zhidong Liu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Shuai Fan
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Yuanquan Chen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China
| | - Yanfeng Wu
- Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen 518000, PR China
| | - Wenjie Liu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China.
| | - Huiyong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China.
| | - Guan Zheng
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, 3025# Shennan Road, Shenzhen, 518000, PR China.
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14
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Yasuda E, Kawamura Y, Ueda Y, Takakura M, Matsuzaka Y, Matsuzaka S, Inohaya A, Chigusa Y, Mandai M, Mogami H. Potential mechanisms for chorioamniotic membrane rupture after subchorionic hematoma. Am J Obstet Gynecol 2025:S0002-9378(25)00064-X. [PMID: 39892838 DOI: 10.1016/j.ajog.2025.01.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/30/2024] [Revised: 01/17/2025] [Accepted: 01/24/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND Subchorionic hematoma is a risk factor for preterm prelabor rupture of membranes and preterm birth. A small proportion of persistent subchorionic hematoma leads to a chronic abruption-oligohydramnios sequence. OBJECTIVE To determine the mechanism by which subchorionic hematomas may damage chorioamniotic membranes. STUDY DESIGN 1) The number and subtype of macrophages were determined by immunohistochemistry in chorioamniotic membranes from 8 subchorionic hematoma patients who delivered preterm (25.5 (24-32) weeks of gestation (median and range)) and 6 gestational age-matched control patients (25.5 (25-28) weeks of gestation (median and range)). Further, the thickness and fibrosis of the membranes were quantified. 2) We also developed an intrauterine hematoma model in pregnant mice, and the effects of hematoma on the amnion were analyzed by histology and immunofluorescence. 3) In vitro, primary human amnion mesenchymal cells were cocultured with M2-differentiated macrophages, and changes in mesenchymal cells were analyzed. RESULTS 1) Subchorionic hematoma increased the number of iron-laden macrophages in the human amnion. These macrophages were CD206+, a marker of macrophages required for the maintenance of homeostasis, tissue remodeling, and metabolic adaptations. The collagen layer of the amnion tended to be thickened in patients with subchorionic hematoma. Interestingly, α-smooth muscle actin+ myofibroblasts were increased in the amnion mesenchymal layer in patients with subchorionic hematoma. Vimentin, a mesenchymal marker, was expressed in the epithelial layer of the hematoma amnion. Together, these findings indicate epithelial-mesenchymal transition in the amnion of membranes from pregnancies with subchorionic hematomas. 2) These findings in human amnion were confirmed in a mouse model of intrauterine hematoma. 3) Further, in vitro, coculture of human amnion mesenchymal cells with M2-differentiated human macrophages resulted in transformation of these cells into α-smooth muscle actin-expressing myofibroblasts via the TGF-β‒Smad3 pathway. CONCLUSION Subchorionic hematoma induces migration of macrophages to chorioamniotic membranes which activate the transition of amnion mesenchymal cells to myofibroblasts. These myofibroblasts may contribute to fibrosis of the amnion and damage chorioamniotic membranes.
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Affiliation(s)
- Eriko Yasuda
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yosuke Kawamura
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yusuke Ueda
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masahito Takakura
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yu Matsuzaka
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Sunao Matsuzaka
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Asako Inohaya
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshitsugu Chigusa
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masaki Mandai
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Haruta Mogami
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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15
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Zhao J, Zhang S, Gong Z, Mao W, Bao W, Li Q, Bai Y, Gao F, Feng S. NLRP3: a key regulator of skin wound healing and macrophage-fibroblast interactions in mice. Cell Commun Signal 2025; 23:55. [PMID: 39881348 PMCID: PMC11780867 DOI: 10.1186/s12964-025-02063-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/29/2024] [Accepted: 01/22/2025] [Indexed: 01/31/2025] Open
Abstract
Wound healing is a highly coordinated process driven by intricate molecular signaling and dynamic interactions between diverse cell types. Nod-like receptor pyrin domain-containing protein 3 (NLRP3) has been implicated in the regulation of inflammation and tissue repair; however, its specific role in skin wound healing remains unclear. This study highlights the pivotal role of NLRP3 in effective skin wound healing, as demonstrated by delayed wound closure and altered cellular and molecular responses in NLRP3-deficient (NLRP3-/-) mice. Histological analysis revealed impaired healing processes, accompanied by reduced expression of key inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2). Deficiencies in apoptosis were evident through altered expression of cysteine-aspartic acid protease 3 (Caspase-3), P53, and B-cell lymphoma-2 (Bcl-2). Furthermore, critical growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and matrix metalloproteinase-9 (MMP-9) were significantly decreased at the excisional skin wound sites. Furthermore, using co-culture systems, we found that NLRP3 mediated the interaction between macrophages and myofibroblasts. Wild-type fibroblast-conditioned media (MFbCM) enhanced nitric oxide (NO), IL-6, and tumor necrosis factor-α (TNF-α) production in M1 macrophages and arginase activity, chitinase 3-like protein 1 (Ym1), and IL-10 expression in M2 macrophages, effects significantly diminished with NLRP3-/- MFbCM. Similarly, conditioned media from wild-type M1 or M2 macrophages promoted the expression of FGF-2, VEGF, and MMP-2 expression in myofibroblasts, which was attenuated when using NLRP3-/- macrophage-conditioned media. PGE2 levels were reduced in both NLRP3-/- macrophages and myofibroblasts. Supplementing NLRP3-/- conditioned media with PGE2 partially restored the impaired functions, suggesting that PGE2 acts as a downstream mediator of NLRP3-regulated macrophage-myofibroblast interactions. These findings indicate that NLRP3 is a key regulator of skin wound healing, facilitating macrophage-myofibroblast communication.
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Affiliation(s)
- Jiamin Zhao
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Shuangyi Zhang
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China.
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China.
| | - Zhiguo Gong
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Wei Mao
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Wenhui Bao
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Qianru Li
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Yunjie Bai
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Feifei Gao
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Shuang Feng
- Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 306, Zhaowuda Road, Hohhot, 010018, China.
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China.
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16
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Zhao S, Kong H, Qi D, Qiao Y, Li Y, Cao Z, Wang H, He X, Liu H, Yang H, Gao S, Liu T, Xie J. Epidermal stem cell derived exosomes-induced dedifferentiation of myofibroblasts inhibits scarring via the miR-203a-3p/PIK3CA axis. J Nanobiotechnology 2025; 23:56. [PMID: 39881312 PMCID: PMC11776291 DOI: 10.1186/s12951-025-03157-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/25/2024] [Accepted: 01/22/2025] [Indexed: 01/31/2025] Open
Abstract
Hypertrophic scar (HS) is a common fibroproliferative disorders with no fully effective treatments. The conversion of fibroblasts to myofibroblasts is known to play a critical role in HS formation, making it essential to identify molecules that promote myofibroblast dedifferentiation and to elucidate their underlying mechanisms. In this study, we used comparative transcriptomics and single-cell sequencing to identify key molecules and pathways that mediate fibrosis and myofibroblast transdifferentiation. Epidermal stem cell-derived extracellular vesicles (EpiSC-EVs) were isolated via ultracentrifugation and filtration, followed by miRNA sequencing to identify miRNAs targeting key molecules. After in vitro and in vivo treatment with EpiSC-EVs, we assessed antifibrotic effects through scratch assays, collagen contraction assays, Western blotting, and immunofluorescence. Transcriptomic sequencing and rescue experiments were used to investigate the molecular mechanism by which miR-203a-3p in EpiSC-EVs induces myofibroblast dedifferentiation. Our results indicate that PIK3CA is overexpressed in HS tissues and positively correlates with fibrosis. EpiSC-EVs were absorbed by scar-derived fibroblasts, promoting dedifferentiation from myofibroblasts to quiescent fibroblasts. Mechanistically, miR-203a-3p in EpiSC-EVs plays an essential role in inhibiting PIK3CA expression and PI3K/AKT/mTOR pathway hyperactivation, thereby reducing scar formation. In vivo studies confirmed that EpiSC-EVs attenuate excessive scarring through the miR-203a-3p/PIK3CA axis, suggesting EpiSC-EVs as a promising therapeutic approach for HS.
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Affiliation(s)
- Shixin Zhao
- Department of Traumatic Orthopedics, Henan Provincial People's Hospital & The People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
- Henan Orthopedics Research Institute, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
- Department of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Haoran Kong
- Department of Traumatic Orthopedics, Henan Provincial People's Hospital & The People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
- Henan Orthopedics Research Institute, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
| | - Dahu Qi
- Department of Traumatic Orthopedics, Henan Provincial People's Hospital & The People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
- Henan Orthopedics Research Institute, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
| | - Yushuang Qiao
- Department of Traumatic Orthopedics, Henan Provincial People's Hospital & The People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
- Henan Orthopedics Research Institute, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
| | - Yu Li
- Department of Traumatic Orthopedics, Henan Provincial People's Hospital & The People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
- Henan Orthopedics Research Institute, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
| | - Zhiming Cao
- Department of Traumatic Orthopedics, Henan Provincial People's Hospital & The People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
- Henan Orthopedics Research Institute, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China
| | - Hanwen Wang
- Department of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Xuefeng He
- Department of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Hengdeng Liu
- Department of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Hao Yang
- Department of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Suyue Gao
- Department of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China
| | - Tao Liu
- Department of Traumatic Orthopedics, Henan Provincial People's Hospital & The People's Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China.
- Henan Orthopedics Research Institute, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, China.
| | - Julin Xie
- Department of Burns, Wound Repair and Reconstruction, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
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17
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Al Mamun A, Shao C, Geng P, Wang S, Xiao J. Recent advances in the role of neuroregulation in skin wound healing. BURNS & TRAUMA 2025; 13:tkae072. [PMID: 39872039 PMCID: PMC11770601 DOI: 10.1093/burnst/tkae072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 05/17/2024] [Revised: 10/24/2024] [Accepted: 11/01/2024] [Indexed: 01/29/2025]
Abstract
Neuroregulation during skin wound healing involves complex interactions between the nervous system and intricate tissue repair processes. The skin, the largest organ, depends on a complex system of nerves to manage responses to injury. Recent research has emphasized the crucial role of neuroregulation in maximizing wound healing outcomes. Recently, researchers have also explained the interactive contact between the peripheral nervous system and skin cells during the different phases of wound healing. Neurotransmitters and neuropeptides, once observed as simple signalling molecules, have since been recognized as effective regulators of inflammation, angiogenesis, and cell proliferation. The significance of skin innervation and neuromodulators is underscored by the delayed wound healing observed in patients with diabetes and the regenerative capabilities of foetal skin. Foetal skin regeneration is influenced by the neuroregulatory environment, immature immune system, abundant growth factors, and increased pluripotency of cells. Foetal skin cells exhibit greater flexibility and specialized cell types, and the extracellular matrix composition promotes regeneration. The extracellular matrix composition of foetal skin promotes regeneration, making it more capable than adult skin because neuroregulatory signals affect skin regeneration. The understanding of these systems can facilitate the development of therapeutic strategies to alter the nerve supply to the skin to enhance the process of wound healing. Neuroregulation is being explored as a potential therapeutic strategy for enhancing skin wound repair. Bioelectronic strategies and neuromodulation techniques can manipulate neural signalling, optimize the neuroimmune axis, and modulate inflammation. This review describes the function of skin innervation in wound healing, emphasizing the importance of neuropeptides released by sensory and autonomic nerve fibres. This article discusses significant discoveries related to neuroregulation and its impact on skin wound healing.
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Affiliation(s)
- Abdullah Al Mamun
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuxiao Shao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Peiwu Geng
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Shuanghu Wang
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Jian Xiao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
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18
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Nair V, Demitri C, Thankam FG. Competitive signaling and cellular communications in myocardial infarction response. Mol Biol Rep 2025; 52:129. [PMID: 39820809 PMCID: PMC11739196 DOI: 10.1007/s11033-025-10236-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/08/2024] [Accepted: 01/07/2025] [Indexed: 01/19/2025]
Abstract
Cell communication and competition pathways are malleable to Myocardial Infarction (MI). Key signals, transcriptive regulators, and metabolites associated with apoptotic responses such as Myc, mTOR, and p53 are important players in the myocardium. The individual state of cardiomyocytes, fibroblasts, and macrophages in the heart tissue are adaptable in times of stress. The overlapping communication pathways of Wnt/β-catenin, Notch, and c-Kit exhibit the involvement of important factors in cell competition in the myocardium. Depending on the effects of these pathways on genetic expression and signal amplification, the proliferative capacities of the previously stated cells that make up the myocardium, amplify or diminish. This creates a distinct classification of "fit" and "unfit" cells. Beyond straightforward traits, the intricate metabolite interactions between neighboring cells unveil a complex battle. Strategic manipulation of these pathways holds translational promise for rapid cardiac recovery post-trauma.
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Affiliation(s)
- Vishnu Nair
- Department of Molecular, Cell, & Developmental Biology, University of California, Los Angeles, CA, 90095, USA
| | - Christian Demitri
- Department of Experimental Medicine, University of Salento, Lecce, 73100, Italy
| | - Finosh G Thankam
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA.
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Xiao X, Huang G, Yu X, Tan Y. Advances in Selenium and Related Compounds Inhibiting Multi-Organ Fibrosis. Drug Des Devel Ther 2025; 19:251-265. [PMID: 39830783 PMCID: PMC11742456 DOI: 10.2147/dddt.s488226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/23/2024] [Accepted: 12/03/2024] [Indexed: 01/22/2025] Open
Abstract
Selenium (Se), a critically essential trace element, plays a crucial role in diverse physiological processes within the human body, such as oxidative stress response, inflammation regulation, apoptosis, and lipid metabolism. Organ fibrosis, a pathological condition caused by various factors, has become a significant global health issue. Numerous studies have demonstrated the substantial impact of Se on fibrotic diseases. This review delves into the latest research advancements in Se and Se-related biological agents for alleviating fibrosis in the heart, liver, lungs, and kidneys, detailing their mechanisms of action within fibrotic pathways. Additionally, the article summa-rizes some of the anti-fibrotic drugs currently in clinical trials for the aforementioned organ fibroses.
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Affiliation(s)
- Xixi Xiao
- The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Minzu University, Enshi, 445000, People’s Republic of China
| | - Guoquan Huang
- Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, People’s Republic of China
- Hubei Provincial Key Laboratory of Selenium Resources and Bioapplications, Enshi, 445000, People’s Republic of China
| | - Xinqiao Yu
- Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, People’s Republic of China
| | - Yong Tan
- Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, People’s Republic of China
- Hubei Provincial Key Laboratory of Selenium Resources and Bioapplications, Enshi, 445000, People’s Republic of China
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20
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Peng H, Chao Z, Wang Z, Hao X, Xi Z, Ma S, Guo X, Zhang J, Zhou Q, Qu G, Gao Y, Luo J, Wang Z, Wang J, Li L. Biomechanics in the tumor microenvironment: from biological functions to potential clinical applications. Exp Hematol Oncol 2025; 14:4. [PMID: 39799341 PMCID: PMC11724500 DOI: 10.1186/s40164-024-00591-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/16/2024] [Accepted: 12/10/2024] [Indexed: 01/15/2025] Open
Abstract
Immune checkpoint therapies have spearheaded drug innovation over the last decade, propelling cancer treatments toward a new era of precision therapies. Nonetheless, the challenges of low response rates and prevalent drug resistance underscore the imperative for a deeper understanding of the tumor microenvironment (TME) and the pursuit of novel targets. Recent findings have revealed the profound impacts of biomechanical forces within the tumor microenvironment on immune surveillance and tumor progression in both murine models and clinical settings. Furthermore, the pharmacological or genetic manipulation of mechanical checkpoints, such as PIEZO1, DDR1, YAP/TAZ, and TRPV4, has shown remarkable potential in immune activation and eradication of tumors. In this review, we delved into the underlying biomechanical mechanisms and the resulting intricate biological meaning in the TME, focusing mainly on the extracellular matrix, the stiffness of cancer cells, and immune synapses. We also summarized the methodologies employed for biomechanical research and the potential clinical translation derived from current evidence. This comprehensive review of biomechanics will enhance the understanding of the functional role of biomechanical forces and provide basic knowledge for the discovery of novel therapeutic targets.
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Affiliation(s)
- Hao Peng
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
- The Second Clinical School, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Zheng Chao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Zefeng Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiaodong Hao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Zirui Xi
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
- The Second Clinical School, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Sheng Ma
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Xiangdong Guo
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Junbiao Zhang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Qiang Zhou
- Department of Urology, Qinghai University Affiliated Hospital, Qinghai University Medical College, Xining, 810001, Qinghai, China
| | - Guanyu Qu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
- The Second Clinical School, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Yuan Gao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
- The Second Clinical School, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China
| | - Jing Luo
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhihua Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China.
- Taikang Tongji (Wuhan) Hospital, 420060, Wuhan, China.
| | - Jing Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China.
| | - Le Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430300, China.
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Zhang F, Hu Z, Jacob A, Brenner M, Wang P. An eCIRP inhibitor attenuates fibrosis and ferroptosis in ischemia and reperfusion induced chronic kidney disease. Mol Med 2025; 31:11. [PMID: 39794717 PMCID: PMC11724597 DOI: 10.1186/s10020-025-01071-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/22/2024] [Accepted: 01/07/2025] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a leading cause of death in the United States, and renal fibrosis represents a pathologic hallmark of CKD. Extracellular cold-inducible RNA-binding protein (eCIRP) is a stress response protein involved in acute inflammation, tissue injury and regulated cell death. However, the role of eCIRP in chronic inflammation and tissue injury has not been elucidated. We hypothesize that eCIRP is involved in renal ischemia/reperfusion (RIR)-induced CKD and that C23, an antagonist to eCIRP, is beneficial in attenuating renal fibrosis and ferroptosis in RIR-induced CKD. METHODS C57BL/6 (WT) or CIRP-/- mice underwent renal injury with total blockage of blood perfusion by clamping bilateral renal pedicles for 28 min. In the WT mice at the time of reperfusion, they were treated with C23 (8 mg/kg) or vehicle. Blood and kidneys were harvested for further analysis at 21 days thereafter. In a separate cohort, mice underwent bilateral RIR and treatment with C23 or vehicle and were then subjected to left nephrectomy 72 h thereafter. Mice were then monitored for additional 19 days, and glomerular filtration rate (GFR) was assessed using a noninvasive transcutaneous method. RESULTS In the RIR-induced CKD, CIRP-/- mice showed decreased collagen deposition, fibronectin staining, and renal injury as compared to the WT mice. Administration of C23 ameliorated renal fibrosis by decreasing the expression of active TGF-β1, α-SMA, collagen deposition, fibronectin and macrophage infiltration to the kidneys. Furthermore, intervention with C23 significantly decreased renal ferroptosis by reducing iron accumulation, increasing the expression of glutathione peroxidase 4 (GPX4) and lipid peroxidation in the kidneys of RIR-induced CKD mice. Treatment with C23 also attenuated BUN and creatinine. Finally, GFR was significantly decreased in RIR mice with left nephrectomy and C23 treatment partially prevented their decrease. CONCLUSION Our data show that eCIRP plays an important role in RIR-induced CKD. Treatment with C23 decreased renal inflammation, alleviated chronic renal injury and fibrosis, and inhibited ferroptosis in the RIR-induced CKD mice.
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Affiliation(s)
- Fangming Zhang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- TheraSource LLC, 350 Community Drive, Manhasset, NY, USA
| | - Zhijian Hu
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Asha Jacob
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, NY, USA
| | - Max Brenner
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
- TheraSource LLC, 350 Community Drive, Manhasset, NY, USA.
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, NY, USA.
| | - Ping Wang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, NY, USA.
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22
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Yu Y, Fang J, Li Y, Wang X, Zhang J, Wang J, Sun B. The Novel Effect and Potential Mechanism of Lactoferrin on Organ Fibrosis Prevention. Nutrients 2025; 17:197. [PMID: 39796631 PMCID: PMC11723014 DOI: 10.3390/nu17010197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/10/2024] [Revised: 12/30/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Organ fibrosis is gradually becoming a human health and safety problem, and various organs of the body are likely to develop fibrosis. The ultimate pathological feature of numerous chronic diseases is fibrosis, and few interventions are currently available to specifically target the pathogenesis of fibrosis. The medical detection of organ fibrosis has gradually matured. However, there is currently no effective treatment method for these diseases. Therefore, we need to strive for developing effective and reliable drugs or substances to treat and prevent fibrotic diseases. Lactoferrin (LF) is a multifunctional glycoprotein with many pathological and physiologically active effects, such as antioxidant, anti-inflammatory and antimicrobial effects, and it protects against pathological and physiological conditions in various disease models. This review summarizes the effects and underlying mechanisms of LF in preventing organ fibrosis. As a naturally active substance, LF can be used as a promising and effective drug for the prevention and remission of fibrotic diseases.
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Affiliation(s)
| | | | | | | | - Jingjie Zhang
- Key Laboratory of Geriatric Nutrition and Health, Ministry of Education, China-Canada Joint Lab of Food Nutrition and Health, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Beijing Technology and Business University, Beijing 100048, China; (Y.Y.); (J.F.); (Y.L.); (X.W.); (B.S.)
| | - Jing Wang
- Key Laboratory of Geriatric Nutrition and Health, Ministry of Education, China-Canada Joint Lab of Food Nutrition and Health, Key Laboratory of Special Food Supervision Technology for State Market Regulation, Beijing Technology and Business University, Beijing 100048, China; (Y.Y.); (J.F.); (Y.L.); (X.W.); (B.S.)
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23
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Varanda RV, Kumari J, van Rheden REM, Cuijpers VMJI, Bloemen M, Göllesch F, Von den Hoff JW, Henneman S, Xie R, Wagener FADTG, Suttorp CM. Survival of periodontal ligament myofibroblasts after short-term mechanical strain in rats and in vitro: Could myofibroblasts contribute to orthodontic relapse? Arch Oral Biol 2025; 172:106173. [PMID: 39778331 DOI: 10.1016/j.archoralbio.2025.106173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/07/2024] [Revised: 12/16/2024] [Accepted: 01/04/2025] [Indexed: 01/11/2025]
Abstract
OBJECTIVES To investigate in vivo whether myofibroblasts formed in the PDL after exposure to short-term high experimental orthodontic forces in rats survive. To study in vitro whether human PDL fibroblasts can differentiate into myofibroblasts and survive when chemical or mechanical stimuli are removed. DESIGN Nine 6-week-old male Wistar rats were used in this experiment. Rat molars were exposed to high but rapidly decreasing experimental orthodontic forces by applying a rubber band and analyzed for the presence of myofibroblasts using ASMA staining. In vitro, human periodontal ligament (PDL) fibroblasts were exposed to transforming growth factor β1 (TGFβ1) and/or mechanical stress and monitored for myofibroblast formation and survival after these stimuli were abrogated. RESULTS In vivo exposure to orthodontic forces strongly induced myofibroblast formation in the stretched regions of the PDL. Furthermore, many PDL myofibroblasts remained present 6 days after exposure to these short-term high orthodontic forces. Human PDL fibroblasts were shown to differentiate into myofibroblasts after 2 days of TGFβ1 exposure and survive for at least 2 more days after removing chemical stimuli (TGFβ1) or mechanical strain. Under in vitro conditions, both TGFβ1 and mechanical strain for 3 days promoted (myo)fibroblast formation, and these cells persisted for 3 more days after the removal of both stimuli. CONCLUSIONS PDL myofibroblasts survive after the removal of mechanical strain in vivo and in vitro. This supports the hypothesis that myofibroblasts, which form in response to mechanical strain and chemical cues in the periodontal ligament (PDL), play a role in relapse following orthodontic tooth movement.
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Affiliation(s)
- Raquel Veloso Varanda
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands
| | - Jyoti Kumari
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands; Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, the Netherlands
| | - René E M van Rheden
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands
| | - Vincent M J I Cuijpers
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands
| | - Marjon Bloemen
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands
| | - Fleur Göllesch
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands
| | - Johannes W Von den Hoff
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands
| | - Sjoerd Henneman
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands
| | - Rui Xie
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands
| | - Frank A D T G Wagener
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands.
| | - C Maarten Suttorp
- Department of Dentistry-Orthodontics and Craniofacial Biology, Research Institute for Medical Innovation, Radboud university medical center, Philips van Leydenlaan 25, Nijmegen 6525 EX, the Netherlands.
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Guan J, Chen K, Lu F, He Y. Dissolving microneedle patch loaded with adipokines-enriched adipose extract relieves atopic dermatitis in mouse via modulating immune disorders, microbiota imbalance, and skin barrier defects. J Tissue Eng 2025; 16:20417314241312511. [PMID: 39917589 PMCID: PMC11800253 DOI: 10.1177/20417314241312511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/29/2024] [Accepted: 12/23/2024] [Indexed: 02/09/2025] Open
Abstract
Atopic dermatitis (AD) is a chronic relapsing dermatosis that demands new therapies. This research group previously developed a physically extracted adipose-derived extracellular matrix named adipose collagen fragments (ACF), which was determined containing massive adipose matrix-bound adipokines and medicable on AD through intradermal injection. However, problems concerning the control of drug release and inevitable pain caused by injection hinder the application of ACF in clinics. Microneedle (MN) is a rapid developing technique for precise and painless transdermal drug delivery. Therefore, a dissolving methacrylated gelatin/hyaluronic acid MN patch loaded with ACF was developed in this study. The morphological characteristics, mechanical properties, penetration ability, as well as biocompatibility and degradation efficiency of ACF-MN were evaluated, and its efficacy on ovalbumin-induced AD mice was also investigated. ACF-MN exhibited excellent penetration ability, biocompatibility, degradation efficiency, and satisfying efficacy on murine AD similar with fresh-made ACF. Furthermore, RNA-Seq combining bioinformatics were performed for mechanism exploration. ACF treatment showed a comprehensive efficacy on AD via restoring inflammatory dysregulation, microbiota imbalance, and skin barrier defects. This study offered a novel MN-based ACF-bound adipokines transdermal delivery system that may serve as a promising strategy for relieving AD.
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Affiliation(s)
| | | | - Feng Lu
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yunfan He
- Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China
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Watanabe M, Tsugeno Y, Sato T, Higashide M, Umetsu A, Furuhashi M, Ohguro H. Inhibition of mTOR differently modulates planar and subepithelial fibrogenesis in human conjunctival fibroblasts. Graefes Arch Clin Exp Ophthalmol 2025; 263:33-46. [PMID: 39042147 DOI: 10.1007/s00417-024-06481-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/11/2023] [Revised: 03/22/2024] [Accepted: 04/01/2024] [Indexed: 07/24/2024] Open
Abstract
PURPOSE In the current investigation, the effects of the mTOR inhibitors, Rapa and Torin1 on the TGF-β2-induced conjunctival fibrogenesis were studied. STUDY DESIGN Experimental research. METHODS 2D and 3D cultures of HconF were subjected to the following analyses; (1) planar proliferation evaluated by TEER (2D), (2) Seahorse metabolic analyses (2D), (3) subepithelial proliferation evaluated by the 3D spheroids' size and hardness, and (4) the mRNA expression of ECM proteins and their regulators (2D and 3D). RESULT Rapa or Torin1 both significantly increased planar proliferation in the non-TGF-β2-treated 2D HconF cells, but in the TGF-β2-treated cells, this proliferation was inhibited by Rapa and enhanced by Torin1. Although Rapa or Torin1 did not affect cellular metabolism in the non-TGF-β2-treated HconF cells, mTOR inhibitors significantly decreased and increased the mitochondrial respiration and the glycolytic capacity, respectively, under conditions of TGF-β2-induced fibrogenesis. Subepithelial proliferation, as evidenced by the hardness of the 3D spheroids, was markedly down-regulated by both Rapa and Torin1 independent of TGF-β2. The mRNA expressions of several ECM molecules and their regulators fluctuated in the cases of 2D vs 3D and TGF-β2 untreated vs treated cultures. CONCLUSION The present findings indicate that mTOR inhibitors have the ability to increase and to reduce planar and subepithelial proliferation in HconF cells, depending on the inhibitor being used.
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Affiliation(s)
- Megumi Watanabe
- Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo Ika Daigaku, Hirosaki, Japan.
| | - Yuri Tsugeno
- Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo Ika Daigaku, Hirosaki, Japan
| | - Tatsuya Sato
- Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo Ika Daigaku, Hirosaki, Japan
- Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo Ika Daigaku, Hirosaki, Japan
| | - Megumi Higashide
- Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo Ika Daigaku, Hirosaki, Japan
| | - Araya Umetsu
- Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo Ika Daigaku, Hirosaki, Japan
| | - Masato Furuhashi
- Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo Ika Daigaku, Hirosaki, Japan
| | - Hiroshi Ohguro
- Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo Ika Daigaku, Hirosaki, Japan.
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26
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Paschall L, Tsai A, Tabdanov E, Negrini K, Izer J, Dhawan A, Szczesny SE. Allograft and autograft anterior cruciate ligament reconstructions exhibit a similar biological response to cyclic loading. Connect Tissue Res 2025; 66:37-48. [PMID: 39988893 DOI: 10.1080/03008207.2025.2456957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/22/2024] [Accepted: 01/15/2025] [Indexed: 02/25/2025]
Abstract
OBJECTIVE Anterior cruciate ligament (ACL) reconstruction is one of the most commonly performed orthopaedic procedures. While outcomes are similar in the general patient population, the rerupture rate of non-irradiated allografts are 3-4 times higher than autografts in young active individuals. Previous studies suggest that the difference in clinical performance between graft types is due to impaired remodeling in allografts in response to loading. The objective of this study was to compare the remodeling response of autografts and allografts to cyclic loading. Furthermore, given that allografts are a foreign object and that immune cell signaling affects fibroblast mechanobiology, we compared markers of the immune cell composition between graft types. METHODS ACL reconstructions were performed on New Zealand white rabbits, harvested 8 weeks post-surgery, and cyclically loaded to 2 MPa in a tensile bioreactor. Expression of markers for anabolic and catabolic tissue remodeling, as well as inflammatory cytokines and immune cells, were quantified using quantitative reverse transcription polymerase chain reaction. RESULTS We found that the expression of markers for tissue remodeling were not different between allografts and autografts. Similarly, we found that the expression of markers for immune cells were not different between allografts and autografts. CONCLUSIONS These data suggest that the poor clinical outcomes and impaired remodeling of allograft reconstructions compared to autografts is not due to a difference in graft mechanobiology.
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Affiliation(s)
- Lauren Paschall
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, USA
| | - Ariane Tsai
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, USA
| | - Erdem Tabdanov
- Department of Pharmacology, The Pennsylvania State University, Hershey, PA, USA
| | - Kara Negrini
- Department of Comparative Medicine, The Pennsylvania State University, Hershey, PA, USA
| | - Jenelle Izer
- Department of Comparative Medicine, The Pennsylvania State University, Hershey, PA, USA
| | - Aman Dhawan
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University, Hershey, PA, USA
| | - Spencer E Szczesny
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, USA
- Department of Orthopaedics and Rehabilitation, The Pennsylvania State University, Hershey, PA, USA
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27
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Wang Q, Pan G, Zhang Y, Ni Y, Mu Y, Luo D. Emerging insights into thyroid cancer from immunotherapy perspective: A bibliometric analysis. Hum Vaccin Immunother 2024; 20:2403170. [PMID: 39294892 DOI: 10.1080/21645515.2024.2403170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/19/2024] [Revised: 08/21/2024] [Accepted: 09/07/2024] [Indexed: 09/21/2024] Open
Abstract
Thyroid cancer is a common endocrine malignancy that poses considerable therapeutic challenges in treating anaplastic carcinoma and advanced aggressive disease. Immunotherapy has become a prominent strategy for cancer treatment, and has shown remarkable advancements in recent years. In this study, we utilized visualization and bibliometric tools to analyze publications on thyroid cancer immunotherapy from the Web of Science Core Collection (WoSCC). A total of 409 articles were included, with an annual increase in both publications and citations since 2016. China leads research efforts in this area, while the University of Texas System and UTMD Anderson Cancer Center rank first in publication output. The journal Thyroid has garnered the highest citations. Notable authors contributing to this field include Antonelli Alessandro, Fallahi Poupak, and Wang Yu. Current research hotspots include immune checkpoint inhibitors, combination therapies involving immunotherapy with targeted therapy, CAR-T cell therapy, and modulation of the tumor microenvironment, all of which underscore the evolving landscape and potential for innovative treatments in thyroid cancer.
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Affiliation(s)
- Qianyu Wang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China
| | - Gang Pan
- Department of Oncological Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Yu Zhang
- Department of Oncological Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Yiqin Ni
- Department of Oncological Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Yuzhu Mu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China
| | - Dingcun Luo
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, Zhejiang, China
- Department of Oncological Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
- College of Mathematical Medicine, Zhejiang Normal University, Jinhua, Zhejiang, China
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Ji A, Davies J, Phan PT, Nguyen CC, Sharma B, Zhu K, Nicotra E, Wan J, Phan HP, Hayward C, Lovell NH, Do TN. Development of a Self-Deploying Extra-Aortic Compression Device for Medium-Term Hemodynamic Stabilization: A Feasibility Study. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024:e2412120. [PMID: 39731354 DOI: 10.1002/advs.202412120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 09/29/2024] [Revised: 12/15/2024] [Indexed: 12/29/2024]
Abstract
Hemodynamic stabilization is crucial in managing acute cardiac events, where compromised blood flow can lead to severe complications and increased mortality. Conditions like decompensated heart failure (HF) and cardiogenic shock require rapid and effective hemodynamic support. Current mechanical assistive devices, such as intra-aortic balloon pumps (IABP) and extracorporeal membrane oxygenation (ECMO), offer temporary stabilization but are limited to short-term use due to risks associated with prolonged blood contact. This research presents a novel proof-of-concept soft robotic device designed with the aim of achieving low-risk, medium-term counterpulsation therapy. The device employs a nature-inspired growing mechanism for potentially minimally invasive deployment around the ascending aorta, coupled with hydraulic artificial muscles for aortic compression. It demonstrated a maximum stroke volume of 16.48 ± 0.21 mL (SD, n = 5), outperforming all other non-pneumatic extra-aortic devices. In addition, in vitro tests with a mock circulation loop (MCL) show a drop in aortic end-diastolic pressure by 6.32 mmHg and enhance coronary flow under mild aortic stenosis, which attenuate the device's assistive effect. These findings highlight the device's strong potential for optimization as a promising solution to improve outcomes for hemodynamically unstable HF patients.
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Affiliation(s)
- Adrienne Ji
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - James Davies
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Phuoc Thien Phan
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Chi Cong Nguyen
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Bibhu Sharma
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Kefan Zhu
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Emanuele Nicotra
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Jingjing Wan
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Hoang-Phuong Phan
- School of Mechanical and Manufacturing Engineering, Faculty of Engineering, UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Christopher Hayward
- Department of Cardiology, St Vincent's Hospital, Sydney, NSW, 2010, Australia
- St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, 2052, Australia
| | - Nigel H Lovell
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
| | - Thanh Nho Do
- Graduate School of Biomedical Engineering, Faculty of Engineering, and Tyree Institute of Health Engineering (IHealthE), UNSW Sydney, Kensington Campus, Sydney, NSW, 2052, Australia
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Jia Q, Ding Y, Su Z, Chen H, Ye J, Xie D, Wu Y, He H, Peng Y, Ni Y. Cell membrane-camouflaged nanoparticles activate fibroblast-myofibroblast transition to promote skin wound healing. Biofabrication 2024; 17:015036. [PMID: 39657324 DOI: 10.1088/1758-5090/ad9cc4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/27/2024] [Accepted: 12/10/2024] [Indexed: 12/12/2024]
Abstract
The fibroblast-myofibroblast transition marked by extracellular matrix (ECM) secretion and contraction of actomyosin-based stress fibers, plays central roles in the wound healing process. This work aims to utilize the cell membrane-based nanoplatform to improve the outcomes of dysregulated wound healing. The cell membranes of myofibroblasts isolated from mouse skin are used as the camouflage for gold nanoparticles loaded with IL-4 cytokine. The membrane-modified nanoparticles show effective in situ clearance of bacterial infection, and act as the activator in IL-4Rα signaling pathway to induce pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype. Thus, the poor bacteria-clearance and non-stop inflammation in refractory wounds are improved and accelerated. Furthermore, the nanoplatform releases myofibroblast membranes to propel primitive fibroblasts toward the fibroblast-myofibroblast transition in an epigenetic manner. Matrix-production, vascularization, and epithelial regeneration are then initiated, leading to the satisfactory wound closure. Our study devises a new strategy for activating fibroblasts into myofibroblasts under prolonged and continuous exposure to the fibrotic environment, and develops a promising biomimetic nanoplatform for effective treatment of dysregulated chronic wound healing.
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Affiliation(s)
- Qi Jia
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Yijuan Ding
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Ziwen Su
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Heying Chen
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Jialing Ye
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Dafeng Xie
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Yubo Wu
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Haiyan He
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Yanlin Peng
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
| | - Yilu Ni
- The M.O.E. Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, #1 Yixueyuan Road, Yuzhong District, Chongqing 400016, People's Republic of China
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Loganath K, Craig N, Barton A, Joshi S, Anagnostopoulos C, Erba PA, Glaudemans AWJM, Saraste A, Bucerius J, Lubberink M, Gheysens O, Buechel RR, Habib G, Gaemperli O, Gimelli A, Hyafil F, Newby DE, Slart RHJA, Dweck MR. Cardiovascular positron emission tomography imaging of fibroblast activation: A review of the current literature. J Nucl Cardiol 2024:102106. [PMID: 39672296 DOI: 10.1016/j.nuclcard.2024.102106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/10/2024] [Revised: 11/22/2024] [Accepted: 11/29/2024] [Indexed: 12/15/2024]
Abstract
Fibrosis is one of the key healing responses to injury, especially within the heart, where it helps to maintain structural integrity following acute insults such as myocardial infarction. However, if it becomes dysregulated, then fibrosis can become maladaptive, leading to adverse remodelling, impaired cardiac function and heart failure. Fibroblast activation protein is exclusively expressed by activated fibroblasts, the key effector cells of fibrogenesis, and has a unique extracellular domain that is an ideal ligand for novel molecular imaging probes. Fibroblast activation protein inhibitor (FAPI) radiotracers have been developed for positron emission tomography (PET) imaging, demonstrating high selectivity for activated fibroblasts across a range of different pathologies and disparate organ systems. In this review, we will summarise the role of fibroblast activation protein in cardiovascular disease and how FAPI radiotracers might improve the assessment and treatment of patients with cardiovascular diseases.
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Affiliation(s)
- Krithika Loganath
- BHF Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.
| | - Neil Craig
- BHF Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Anna Barton
- BHF Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Shruti Joshi
- BHF Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Constantinos Anagnostopoulos
- Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | - Paola Anna Erba
- Nuclear Medicine, Department of Translational Research and New Technology in Medicine, University of Pisa, Pisa, Italy; Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Andor W J M Glaudemans
- Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Antti Saraste
- Turku PET Centre, Turku University Hospital and University of Turku, Kiinamllynkatu, Turku, Finland; Heart Center, Turku University Hospital, Turku, Finland
| | - Jan Bucerius
- Department of Nuclear Medicine, Georg-August University Göttingen, University Medicine Göttingen, Göttingen, Germany
| | - Mark Lubberink
- Department of Surgical Sciences/Radiology, Uppsala University, Uppsala, Sweden
| | - Olivier Gheysens
- Department of Nuclear Medicine, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Ronny R Buechel
- Department of Nuclear Medicine, Cardiac Imaging, University Hospital Zurich, Zurich, Switzerland
| | - Gilbert Habib
- Cardiology Department, APHM, La Timone Hospital, Marseille, France; Aix Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Oliver Gaemperli
- HeartClinic, Hirslanden Hospital Zurich, Hirslanden, Switzerland
| | | | - Fabien Hyafil
- Department of Nuclear Medicine, DMU IMAGINA, Georges-Pompidou European Hospital, Assistance Publique - Hôpitaux de Paris, University of Paris, Paris, France; PARCC, INSERM, University of Paris, Paris, France
| | - David E Newby
- BHF Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Riemer H J A Slart
- Medical Imaging Centre, Department of Nuclear Medicine & Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Faculty of Science and Technology Biomedical, Photonic Imaging, University of Twente, Enschede, the Netherlands
| | - Marc R Dweck
- BHF Centre of Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
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Doci RSA, Carvalho FFD, Gomes RC, Gianini RJ, Fanelli C, Noronha IDL, Santos NBD, Hausen MDA, Komatsu D, Randazzo-Moura P. Pharmacological effects of triamcinolone associated with surgical glue on cutaneous wound healing in rats. Acta Cir Bras 2024; 39:e399624. [PMID: 39661810 DOI: 10.1590/acb399624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/05/2024] [Accepted: 09/30/2024] [Indexed: 12/13/2024] Open
Abstract
PURPOSE The surgical glue is widely used in closing cutaneous surgical wounds. Corticosteroids are indicated for their anti-inflammatory and immunomodulatory properties. The present work evaluated the pharmacological effects of triamcinolone (AT) incorporated into surgical glue (C) on the initial phase of the wound healing process in Wistar rats. METHODS Through in-vivo studies, the effects of the healing process, C or C+AT in the same rat were evaluated for seven and 14 days post-surgery. RESULTS The C+AT association did not change the physicochemical properties of the polymer. This association in wound healing confirmed the anti-inflammatory and immunomodulatory effects of the corticosteroid, with less neovascularization and fibrosis, in addition to the remodeling of the extracellular matrix carried out by the balance of myofibroblasts and less dense collagen fibers, culminating in tissue regeneration and possible reduction of side effects. CONCLUSION This association is a powerful and innovative pharmacological tool, promising in translational medicine.
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Affiliation(s)
- Rosana Soares Araújo Doci
- Pontifícia Universidade Católica de São Paulo - Faculty of Medical and Health Sciences - Program of Postgraduate in Biomaterials and Regenerative Medicine - São Paulo (SP) - Brazil
| | - Filipe Feitosa de Carvalho
- Pontifícia Universidade Católica de São Paulo - Faculty of Medical and Health Sciences - Program of Postgraduate in Biomaterials and Regenerative Medicine - São Paulo (SP) - Brazil
| | - Rodrigo César Gomes
- Pontifícia Universidade Católica de São Paulo - Faculty of Medical and Health Sciences - Biomaterials Laboratory - São Paulo (SP) - Brazil
| | - Reinaldo José Gianini
- Pontifícia Universidade Católica de São Paulo - Faculty of Medical and Health Sciences - Program of Postgraduate in Biomaterials and Regenerative Medicine - São Paulo (SP) - Brazil
| | - Camilla Fanelli
- Universidade de São Paulo - Medical School - Laboratory of Cellular, Genetic, and Molecular Nephrology - São Paulo (SP) - Brazil
| | - Irene de Lourdes Noronha
- Universidade de São Paulo - Medical School - Laboratory of Cellular, Genetic, and Molecular Nephrology - São Paulo (SP) - Brazil
| | - Nelson Brancaccio Dos Santos
- Pontifícia Universidade Católica de São Paulo - Faculty of Medical and Health Sciences - Pathology Laboratory - São Paulo (SP) - Brazil
| | - Moema de Alencar Hausen
- Pontifícia Universidade Católica de São Paulo - Faculty of Medical and Health Sciences - Program of Postgraduate in Biomaterials and Regenerative Medicine - São Paulo (SP) - Brazil
| | - Daniel Komatsu
- Pontifícia Universidade Católica de São Paulo - Faculty of Medical and Health Sciences - Program of Postgraduate in Biomaterials and Regenerative Medicine - São Paulo (SP) - Brazil
| | - Priscila Randazzo-Moura
- Pontifícia Universidade Católica de São Paulo - Faculty of Medical and Health Sciences - Program of Postgraduate in Biomaterials and Regenerative Medicine - São Paulo (SP) - Brazil
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32
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Nagalingam RS, Jayousi F, Hamledari H, Dababneh S, Hosseini D, Lindsay C, Klein Geltink R, Lange PF, Dixon IM, Rose RA, Czubryt MP, Tibbits GF. Molecular and metabolomic characterization of hiPSC-derived cardiac fibroblasts transitioning to myofibroblasts. Front Cell Dev Biol 2024; 12:1496884. [PMID: 39698493 PMCID: PMC11653212 DOI: 10.3389/fcell.2024.1496884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/15/2024] [Accepted: 11/11/2024] [Indexed: 12/20/2024] Open
Abstract
Background Mechanical stress and pathological signaling trigger the activation of fibroblasts to myofibroblasts, which impacts extracellular matrix composition, disrupts normal wound healing, and can generate deleterious fibrosis. Myocardial fibrosis independently promotes cardiac arrhythmias, sudden cardiac arrest, and contributes to the severity of heart failure. Fibrosis can also alter cell-to-cell communication and increase myocardial stiffness which eventually may lead to lusitropic and inotropic cardiac dysfunction. Human induced pluripotent stem cell derived cardiac fibroblasts (hiPSC-CFs) have the potential to enhance clinical relevance in precision disease modeling by facilitating the study of patient-specific phenotypes. However, it is unclear whether hiPSC-CFs can be activated to become myofibroblasts akin to primary cells, and the key signaling mechanisms in this process remain unidentified. Objective We aim to explore the notable changes in fibroblast phenotype upon passage-mediated activation of hiPSC-CFs with increased mitochondrial metabolism, like primary cardiac fibroblasts. Methods We activated the hiPSC-CFs with serial passaging from passage 0 to 3 (P0 to P3) and treatment of P0 with TGFβ1. Results Passage-mediated activation of hiPSC-CFs was associated with a gradual induction of genes to initiate the activation of these cells to myofibroblasts, including collagen, periostin, fibronectin, and collagen fiber processing enzymes with concomitant downregulation of cellular proliferation markers. Most importantly, canonical TGFβ1 and Hippo signaling component genes including TAZ were influenced by passaging hiPSC-CFs. Seahorse assay revealed that passaging and TGFβ1 treatment increased mitochondrial respiration, consistent with fibroblast activation requiring increased energy production, whereas treatment with the glutaminolysis inhibitor BPTES completely attenuated this process. Conclusion Our study highlights that the hiPSC-CF passaging enhanced fibroblast activation, activated fibrotic signaling pathways, and enhanced mitochondrial metabolism approximating what has been reported in primary cardiac fibroblasts. Thus, hiPSC-CFs may provide an accurate in vitro preclinical model for the cardiac fibrotic condition, which may facilitate the identification of putative anti-fibrotic therapies, including patient-specific approaches.
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Affiliation(s)
- Raghu Sundaresan Nagalingam
- Cellular and Regenerative Medicine Centre, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Farah Jayousi
- Cellular and Regenerative Medicine Centre, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Homa Hamledari
- Cellular and Regenerative Medicine Centre, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Saif Dababneh
- Cellular and Regenerative Medicine Centre, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Dina Hosseini
- Cellular and Regenerative Medicine Centre, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Chloe Lindsay
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
| | - Ramon Klein Geltink
- Cellular and Regenerative Medicine Centre, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, BC, Canada
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Philipp F. Lange
- Cellular and Regenerative Medicine Centre, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Colombia, Vancouver, BC, Canada
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Ian Michael Dixon
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
| | - Robert Alan Rose
- Department of Cardiac Sciences, Cumming School of Medicine, Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
- Department of Physiology and Pharmacology, Cumming School of Medicine, Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Michael Paul Czubryt
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
| | - Glen Findlay Tibbits
- Cellular and Regenerative Medicine Centre, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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Fleckner M, Döhmen NK, Salz K, Christophers T, Windolf J, Suschek CV, Oezel L. Exposure of Primary Human Skin Fibroblasts to Carbon Dioxide-Containing Solution Significantly Reduces TGF-β-Induced Myofibroblast Differentiation In Vitro. Int J Mol Sci 2024; 25:13013. [PMID: 39684728 DOI: 10.3390/ijms252313013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/30/2024] [Revised: 11/21/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Wound healing as a result of a skin injury involves a series of dynamic physiological processes, leading to wound closure, re-epithelialization, and the remodeling of the extracellular matrix (ECM). The primary scar formed by the new ECM never fully regains the original tissue's strength or flexibility. Moreover, in some cases, due to dysregulated fibroblast activity, proliferation, and differentiation, the normal scarring can be replaced by pathological fibrotic tissue, leading to hypertrophic scars or keloids. These disorders can cause significant physical impairment and psychological stress and represent significant challenges in medical management in the wound-healing process. The present study aimed to investigate the therapeutic effects of exogenously applied carbon dioxide (CO2) on fibroblast behavior, focusing on viability, proliferation, migration, and differentiation to myofibroblasts. We found that CO2 exposure for up to 60 min did not significantly affect fibroblast viability, apoptosis rate, or proliferation and migration capacities. However, a notable finding was the significant reduction in α-smooth muscle actin (α-SMA) protein expression, indicative of myofibroblast differentiation inhibition, following CO2 exposure. This effect was specific to CO2 and concentration as well as time-dependent, with longer exposure durations leading to greater reductions in α-SMA expression. Furthermore, the inhibition of myofibroblast differentiation correlated with a statistically significantly reduced glycolytic and mitochondrial energy metabolism, and as a result, with a reduced ATP synthesis rate. This very noticeable decrease in cellular energy levels seemed to be specific to CO2 exposure and could not be observed in the control cultures using nitrogen (N2)-saturated solutions, indicating a unique and hypoxia-independent effect of CO2 on fibroblast metabolism. These findings suggest that exogenously applied CO2 may possess fibroblast differentiation-reducing properties by modulating fibroblast's energy metabolism and could offer new therapeutic options in the prevention of scar and keloid development.
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Affiliation(s)
- Maxine Fleckner
- Department for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Dusseldorf, Germany
| | - Niklas K Döhmen
- Department for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Dusseldorf, Germany
| | - Katharina Salz
- Department for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Dusseldorf, Germany
| | - Till Christophers
- Department for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Dusseldorf, Germany
| | - Joachim Windolf
- Department for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Dusseldorf, Germany
| | - Christoph V Suschek
- Department for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Dusseldorf, Germany
| | - Lisa Oezel
- Department for Orthopedics and Trauma Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Dusseldorf, Germany
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Alakhdar AA, Sivakumar S, Kopchak RM, Hunter AN, Ambrosio F, Washburn NR. Age-Related ECM Stiffness Mediates TRAIL Activation in Muscle Stem Cell Differentiation. Adv Biol (Weinh) 2024; 8:e2400334. [PMID: 39601528 DOI: 10.1002/adbi.202400334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/13/2024] [Revised: 10/01/2024] [Indexed: 11/29/2024]
Abstract
The stiffening of the extracellular matrix (ECM) with age hinders muscle regeneration by causing intrinsic muscle stem cell (MuSC) dysfunction through a poorly understood mechanism. Here, the study aims to study those age-related molecular changes in the differentiation of MuSCs due to age and/or stiffness. Hence, young and aged MuSCs are seeded onto substrates engineered to mimic a soft and stiff ECM microenvironment to study those molecular changes using single-cell RNA sequencing (scRNA). The trajectory of scRNA data of the MuSCs under four different conditions undergoing differentiation is analyzed as well as the active molecular pathways and transcription factors driving those differentiation fates. Data revealed the presence of a branching point within the trajectory leading to the emergence of an age-related fibroblastic population characterized by activation of the TNF-related apoptosis-inducing ligand (TRAIL) pathway, which is significantly activated in aged cells cultured on stiff substrates. Next, using the collagen cross-linking inhibitor β-aminopropionitrile (BAPN) in vivo, the study elucidates stiffness changes on TRAIL downstream apoptotic targets (caspase 8 and caspase 3) using immunostaining. TRAIL activity is significantly inhibited by BAPN in aged animals, indicating a complex mechanism of age-related declines in muscle function through inflammatory and apoptotic mediators.
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Affiliation(s)
- Amira A Alakhdar
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
| | | | - Rylee M Kopchak
- Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding, Boston, MA, 02129, USA
| | - Allison N Hunter
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
| | - Fabrisia Ambrosio
- Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding, Boston, MA, 02129, USA
- Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, 02129, USA
| | - Newell R Washburn
- Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, 15213, USA
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Zhou L, Zhang Y, Yi X, Chen Y, Li Y. Advances in proteins, polysaccharides, and composite biomaterials for enhanced wound healing via microenvironment management: A review. Int J Biol Macromol 2024; 282:136788. [PMID: 39490870 DOI: 10.1016/j.ijbiomac.2024.136788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/12/2024] [Revised: 10/10/2024] [Accepted: 10/20/2024] [Indexed: 11/05/2024]
Abstract
Wound management is crucial yet imposes substantial social and economic burdens on patients and healthcare systems. The recent rapid advancements in biomaterials and manufacturing technology have created favorable conditions for expediting wound healing. This review examines the latest developments in biomacromolecule-based wound dressings, with a particular focus on proteins and polysaccharides, and their role in modulating the wound microenvironment. The importance of extracellular matrix (ECM)-inspired materials, such as hydrogels and biomimetic dressings, is emphasized. Additionally, this review explores the functionalization of wound dressings, emphasizing properties such as hemostatic capabilities, pain relief, antimicrobial activity, and innovative smart functions like electroceuticals and wound condition monitoring. The study integrates discussions on both the macroscopic healing outcomes and the microscopic pathophysiological mechanisms, highlighting recent advances in managing wound environments to expedite healing. Finally, the review critically assesses the challenges associated with the clinical translation of these wound-healing materials in the future.
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Affiliation(s)
- Lingyan Zhou
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ying Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoli Yi
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yining Chen
- Key Laboratory of Leather Chemistry and Engineering (Sichuan University), Ministry of Education, Chengdu 610065, China
| | - Yuwen Li
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China
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Rahaman MS, Arin A, Farwa U, Park M, Bae SH, Lee BT. ECM derivatized alginate augmenting bio-functionalities of lyophilized mat for skin and liver wound treatment. Biomaterials 2024; 311:122698. [PMID: 38968688 DOI: 10.1016/j.biomaterials.2024.122698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/27/2023] [Revised: 06/27/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024]
Abstract
Peptides and molecular residues sourced from the fragmentation of the extracellular matrix (ECM) can exacerbate a plethora of cellular functions. We selected a natural ECM-derived complex peptide mixture to functionalize sodium alginate. Three alginate derivatives (sodium alginate conjugated with ECM) SALE-1, SALE-2, and SALE-3 were synthesized using the lowest (10 % w/w), moderate (50 % w/w), and highest (100 % w/w) concentrations of ECM. Thereafter, they were used to fabricate three groups of mat scaffolds EMAT-1 (ECM derivatized alginate thrombin-mat), EMAT-2, and EMAT-3, respectively by the freeze-drying process. To enhance the hemostatic activity, thrombin was loaded onto the scaffolds. Another group, AT, without any derivatized alginate was additionally included in order to comparative analysis. Physical characteristics revealed that the porous mat scaffold showed enhancement in degradation and swelling ability with the increase in ECM content. The higher cell proliferation, migration, and cell viability were noticed in the higher ECM-containing samples EMAT-2 and EMAT-3. In vivo studies using rodent hepatic and rabbit ear models were carried out to ensure the hemostatic ability of the scaffolds. EMAT-2 and EMAT-3 demonstrate excellent liver regeneration ability in rat models. Moreover, the rat cutaneous wound model depicted that EMAT-3 dramatically elevated the skin's healing ability, thereby rendering it an excellent candidate for future clinical application in wound healing.
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Affiliation(s)
- Md Sohanur Rahaman
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Asuva Arin
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Ume Farwa
- Institute of Tissue Regeneration, Soonchunhyang University, Cheonan-31151, Republic of Korea
| | - Myeongki Park
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Sang Ho Bae
- Department of Surgery, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Republic of Korea
| | - Byong-Taek Lee
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 31151, Republic of Korea; Institute of Tissue Regeneration, Soonchunhyang University, Cheonan-31151, Republic of Korea.
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Ding L, Lin H, Yang Z, Zhang P, Chen X. Polycaprolactone/gelatin-QAS/bioglass nanofibres accelerate diabetic chronic wound healing by improving dysfunction of fibroblasts. Int J Biol Macromol 2024; 283:136699. [PMID: 39442840 DOI: 10.1016/j.ijbiomac.2024.136699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/05/2024] [Revised: 10/09/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024]
Abstract
Worldwide, more than 25 % of patients with diabetes develop chronic diabetic wounds in their lifetime. Infection and dysfunctional fibroblasts represent two significant etiological factors contributing to impaired wound healing in patients with diabetes. It is therefore evident that the development of wound dressings with both anti-infective and DM fibroblast modulating functions has the potential for clinical applications. In this study, a PCL/gelatine-quaternary ammonium salts (QAS)/bioglass (BG) electrospun nanofibrous membrane was developed with physico-chemical and biological properties that not only meet the clinical requirements for wound dressings but also exhibit remarkable moisturising (water adsorption rate of 382.39 ± 4.36 %) and tear-resistance properties (a tear strength of ~5.5 MPa). The incorporation of QAS and BG has enhanced the biocompatibility and bioactivity of the nanofibres, while also imparting remarkable antimicrobial properties. The antibacterial efficacy of PGQ-BG against E. coli and S. aureus was found to be 92.8 ± 0.78 % and 99.3 ± 0.55 %, respectively. Moreover, it was demonstrated that PGQ-BG nanofibers exerted a promoting effect on the extracellular matrix (ECM) in dysfunctional fibroblasts and upregulated the expression level of α-smooth muscle actin (α-SMA), a marker of their differentiation to myofibroblasts in vitro and in vivo. Furthermore, the COL-III/COL-I ratio was significantly increased, indicating that PGQ-BG may also accelerate wound healing. The nanofibrous dressing reduced scar formation by increasing the COL-III/COL-I ratio. This is the first report of BG improving fibroblast dysfunction via COL-III and COL-I promotion in fibroblasts, both in vitro and in vivo. Therefore, this novel bioactive nanofibrous dressing represents an effective and safe therapeutic strategy for improving chronic wound healing in patients with diabetes.
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Affiliation(s)
- Lin Ding
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China; National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou 510006, China; Key Laboratory of Biomedical Engineering of Guangdong Province and Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, China
| | - Hao Lin
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China; National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou 510006, China; Key Laboratory of Biomedical Engineering of Guangdong Province and Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, China
| | - Zhengyu Yang
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China; National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou 510006, China; Key Laboratory of Biomedical Engineering of Guangdong Province and Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, China
| | - Peng Zhang
- School of Stomatology, Zhuhai Campus of Zunyi Medical University, Zhuhai 519040, China.
| | - Xiaofeng Chen
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510641, China; National Engineering Research Centre for Tissue Restoration and Reconstruction, Guangzhou 510006, China; Key Laboratory of Biomedical Engineering of Guangdong Province and Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, China.
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Wang H, You Q, Kang B, Jing H, Shi Z, Krizkova S, Heger Z, Adam V, Chen X, Li N. Pulling the Rug Out from Under: Biomechanical Microenvironment Remodeling for Induction of Hepatic Stellate Cell Quiescence. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2406590. [PMID: 39410721 DOI: 10.1002/adma.202406590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 05/08/2024] [Revised: 08/24/2024] [Indexed: 12/06/2024]
Abstract
Hepatic fibrosis progresses concomitantly with a variety of biomechanical alternations, especially increased liver stiffness. These biomechanical alterations have long been considered as pathological consequences. Recently, growing evidence proposes that these alternations result in the fibrotic biomechanical microenvironment, which drives the activation of hepatic stellate cells (HSCs). Here, an inorganic ascorbic acid-oxidase (AAO) mimicking nanozyme loaded with liquiritigenin (LQ) is developed to trigger remodeling of the fibrotic biomechanical microenvironment. The AAO mimicking nanozyme is able to consume intracellular ascorbic acid, thereby impeding collagen I deposition by reducing its availability. Simultaneously, LQ inhibits the transcription of lysyl oxidase like 2 (LOXL2), thus impeding collagen I crosslinking. Through its synergistic activities, the prepared nanosystem efficiently restores the fibrotic biomechanical microenvironment to a near-normal physiological condition, promoting the quiescence of HSCs and regression of fibrosis. This strategy of remodeling the fibrotic biomechanical microenvironment, akin to "pulling the rug out from under", effectively treats hepatic fibrosis in mice, thereby highlighting the importance of tissue biomechanics and providing a potential approach to improve hepatic fibrosis treatment.
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Affiliation(s)
- Haobo Wang
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072, China
| | - Qing You
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
| | - Bei Kang
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072, China
| | - Huaqing Jing
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072, China
| | - Zhiyuan Shi
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072, China
| | - Sona Krizkova
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, CZ-61300, Czech Republic
| | - Zbynek Heger
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, CZ-61300, Czech Republic
- Center of Advanced Innovation Technologies, Faculty of Materials Science and Technology, VSB - Technical University of Ostrava, Ostrava, CZ-708 00, Czech Republic
| | - Vojtech Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, CZ-61300, Czech Republic
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore
- Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
- Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Nan Li
- Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, 300072, China
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Meloni M, de Rooij B, Janssen FW, Rescigno F, Lombardi B. Targeted Antibacterial Endolysin to Treat Infected Wounds on 3D Full-Thickness Skin Model: XZ.700 Efficacy. Pharmaceutics 2024; 16:1539. [PMID: 39771518 PMCID: PMC11728803 DOI: 10.3390/pharmaceutics16121539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/23/2024] [Revised: 11/15/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025] Open
Abstract
Backgrounds/Objectives: Skin wound healing is a physiological process orchestrated by epithelial and mesenchymal cells able to restore tissue continuity by re-organizing themselves and the ECM. This research study aimed to develop an optimized in vitro experimental model of full-thickness skin, to address molecular and morphological modifications occurring in the re-epithelization and wound healing process. Methods: Wound healing starting events were investigated within an experimental window of 8 days at the molecular level by gene expression and immunofluorescence of key epidermal and dermal biomarkers. To mirror the behavior of infected wounds, the established wound healing model was then colonized with S. aureus, and the efficacy of a novel antibacterial agent, XZ.700, was investigated. Viable counts (CFU/tissue), IF, and ultrastructural analysis (SEM) were performed to evaluate S. aureus colonization inside and around the wound bed in an experimental window of 3 h of colonization and 24 h of treatment. Results: Endolysin showed an efficacy in counteracting bacterial growth and invasion within the wound bed, reducing the S. aureus load compared to its placebo, thanks to its selective antimicrobial activity interfering with biofilm formation. Conclusions: The preclinical in vitro infected wound model on FT-kin showed interesting applications to assess the repair efficacy of dermo-pharmaceutical and cosmetic formulations.
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Affiliation(s)
- Marisa Meloni
- VitroScreen s.r.l., In Vitro Innovation Center, Via Mosè Bianchi 103, 20149 Milan, MI, Italy; (M.M.); (B.L.)
| | - Bob de Rooij
- Micreos Pharmaceuticals, Neuhofstrasse 12, CH-6430 Baar, ZG, Switzerland; (B.d.R.); (F.W.J.)
| | - Ferdinand W. Janssen
- Micreos Pharmaceuticals, Neuhofstrasse 12, CH-6430 Baar, ZG, Switzerland; (B.d.R.); (F.W.J.)
| | - Francesca Rescigno
- VitroScreen s.r.l., In Vitro Innovation Center, Via Mosè Bianchi 103, 20149 Milan, MI, Italy; (M.M.); (B.L.)
| | - Bernadette Lombardi
- VitroScreen s.r.l., In Vitro Innovation Center, Via Mosè Bianchi 103, 20149 Milan, MI, Italy; (M.M.); (B.L.)
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Lee SE, Yu SH, Kim IH, Kang YC, Kim Y, Yeo JS, Lim JH, Kwon I, Kim JH, Park SW, Chang MY, Han K, Kim SH, Kim CH. Mitochondrial Transplantation Ameliorates Pulmonary Fibrosis by Suppressing Myofibroblast Activation. Int J Mol Sci 2024; 25:12783. [PMID: 39684495 DOI: 10.3390/ijms252312783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/06/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a pulmonary disease characterized by excessive extracellular matrix protein deposition in the lung interstitium, subsequently causing respiratory failure. IPF still has a high medical unmet requirement due to the lack of effective treatments to inhibit disease progression. The etiology of IPF remains unclear, but mitochondrial dysfunction is considered to be associated with IPF development. Therefore, targeting mitochondrial abnormalities would be a promising strategy for treating IPF. Recently, exogenous mitochondrial transplantation has been beneficial for treating mitochondrial dysfunction. The current study aimed to examine the therapeutic effect of mitochondrial transplantation on IPF in vitro and in vivo. Mitochondria were isolated from human umbilical cord mesenchymal stem cells, referred to as PN-101. Human lung fibroblasts and human bronchial epithelial cells were exposed to transforming growth factor-β, followed by PN-101 treatment to determine the in vitro efficacy of mitochondrial transplantation. An IPF mouse model established by a single intratracheal instillation of bleomycin was utilized to determine the in vivo efficacy of the intravenously treated mitochondria. PN-101 attenuated mitochondrial damage, inhibited EMC production, and suppressed epithelial-to-mesenchymal transition in vitro. Additionally, intravenous PN-101 administration alleviated bleomycin-induced fibrotic processes in the IPF mouse model with a therapeutic context. Our data indicate that PN-101 is a novel and potential therapeutic agent for IPF.
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Affiliation(s)
- Seo-Eun Lee
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
| | - Shin-Hye Yu
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea
| | - In-Hyeon Kim
- Division of Jeonbuk Advanced Bio Research, Korea Institute of Toxicology, Jeongeup 56212, Republic of Korea
- College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Young Cheol Kang
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
| | - Yujin Kim
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
| | - Jeong Seon Yeo
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
| | - Jun Hyeok Lim
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
| | - Iksun Kwon
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
| | - Je-Hein Kim
- Division of Jeonbuk Advanced Bio Research, Korea Institute of Toxicology, Jeongeup 56212, Republic of Korea
| | - Se-Woong Park
- Division of Jeonbuk Advanced Bio Research, Korea Institute of Toxicology, Jeongeup 56212, Republic of Korea
- College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Mi-Yoon Chang
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea
- Department of Premedicine, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
| | - Kyuboem Han
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
| | - Sung-Hwan Kim
- Division of Jeonbuk Advanced Bio Research, Korea Institute of Toxicology, Jeongeup 56212, Republic of Korea
| | - Chun-Hyung Kim
- Paean Biotechnology, Inc., 5 Samil-daero 8-gil, Jung-gu, Seoul 04552, Republic of Korea
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Rudman-Melnick V, Vanhoutte D, Stowers K, Sargent M, Adam M, Ma Q, Perl AKT, Miethke AG, Burg A, Shi T, Hildeman DA, Woodle ESS, Kofron JM, Devarajan P. Gucy1α1 specifically marks kidney, heart, lung and liver fibroblasts. Sci Rep 2024; 14:29307. [PMID: 39592775 PMCID: PMC11599588 DOI: 10.1038/s41598-024-80930-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/16/2024] [Accepted: 11/22/2024] [Indexed: 11/28/2024] Open
Abstract
Fibrosis is a common outcome of numerous pathologies, including chronic kidney disease (CKD), a progressive renal function deterioration. Current approaches to target activated fibroblasts, key effector contributors to fibrotic tissue remodeling, lack specificity. Here, we report Gucy1α1 as a specific kidney fibroblast marker. Gucy1α1 levels significantly increased over the course of two clinically relevant murine CKD models and directly correlated with established fibrosis markers. Immunofluorescent (IF) imaging showed that Gucy1α1 comprehensively labelled cortical and medullary quiescent and activated fibroblasts in the control kidney and throughout injury progression, respectively. Unlike traditionally used markers platelet derived growth factor receptor beta (Pdgfrβ) and vimentin (Vim), Gucy1α1 did not overlap with off-target populations such as podocytes. Notably, Gucy1α1 labelled kidney fibroblasts in both male and female mice. Furthermore, we observed elevated GUCY1α1 expression in the human fibrotic kidney and lung. Studies in the murine models of cardiac and liver fibrosis revealed Gucy1α1 elevation in activated Pdgfrβ-, Vim- and alpha smooth muscle actin (αSma)-expressing fibroblasts paralleling injury progression and resolution. Overall, we demonstrate Gucy1α1 as an exclusive fibroblast marker in both sexes. Due to its multiorgan translational potential, GUCY1α1 might provide a novel promising strategy to specifically target and mechanistically examine fibroblasts.
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Affiliation(s)
- Valeria Rudman-Melnick
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 268-280 Albert Sabin Way, location T, floor 6, suite 272, Cincinnati, OH, 45229, USA
| | - Davy Vanhoutte
- Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Kaitlynn Stowers
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 268-280 Albert Sabin Way, location T, floor 6, suite 272, Cincinnati, OH, 45229, USA
| | - Michelle Sargent
- Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Mike Adam
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Qing Ma
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 268-280 Albert Sabin Way, location T, floor 6, suite 272, Cincinnati, OH, 45229, USA
| | - Anne Karina T Perl
- Division of Neonatology and Pulmonary biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Alexander G Miethke
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Ashley Burg
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Tiffany Shi
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - David A Hildeman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - E Steve S Woodle
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - J Matthew Kofron
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Prasad Devarajan
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 268-280 Albert Sabin Way, location T, floor 6, suite 272, Cincinnati, OH, 45229, USA.
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McElhinney K, Irnaten M, O’Callaghan J, O’Brien C. p53 and the E3 Ubiquitin Ligase MDM2 in Glaucomatous Lamina Cribrosa Cells. Int J Mol Sci 2024; 25:12173. [PMID: 39596239 PMCID: PMC11595009 DOI: 10.3390/ijms252212173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/24/2024] [Revised: 11/09/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024] Open
Abstract
Lamina cribrosa (LC) cells play an integral role in extracellular matrix remodeling and fibrosis in human glaucoma. LC cells bear similarities to myofibroblasts that adopt an apoptotic-resistant, proliferative phenotype, a process linked to dysregulation of tumor suppressor-gene p53 pathways, including ubiquitin-proteasomal degradation via murine-double-minute-2 (MDM2). Here, we investigate p53 and MDM2 in glaucomatous LC cells. Primary human LC cells were isolated from glaucomatous donor eyes (GLC) and age-matched normal controls (NLC) (n = 3 donors/group). LC cells were cultured under standard conditions ± 48-h treatment with p53-MDM2-interaction inhibitor RG-7112. Markers of p53-MDM2, fibrosis, and apoptosis were analyzed by real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Cellular proliferation and viability were assessed using colorimetric methyl-thiazolyl-tetrazolium salt assays (MTS/MTT). In GLC versus NLC cells, protein expression of p53 was significantly decreased (p < 0.05), MDM2 was significantly increased, and immunofluorescence showed reduced p53 and increased MDM2 expression in GLC nuclei. RG-7112 treatment significantly increased p53 and significantly decreased MDM2 gene and protein expression. GLC cells had significantly increased protein expression of αSMA, significantly decreased caspase-3 protein expression, and significantly increased proliferation after 96 h. RG-7112 treatment significantly decreased COL1A1 and αSMA, significantly increased BAX and caspase-3 gene expression, and significantly decreased proliferation in GLC cells. MTT-assay showed equivocal cellular viability in NLC/GLC cells with/without RG-7112 treatment. Our data suggests that proliferation and the ubiquitin-proteasomal pathway are dysregulated in GLC cells, with MDM2-led p53 protein degradation negatively impacting its protective role.
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Affiliation(s)
- Kealan McElhinney
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
- Department of Ophthalmology, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
| | - Mustapha Irnaten
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
| | - Jeffrey O’Callaghan
- Ocular Genetics Unit, Smurfit Institute of Genetics, Trinity College, University of Dublin, D02 PN40 Dublin, Ireland
| | - Colm O’Brien
- UCD Clinical Research Centre, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
- Department of Ophthalmology, Mater Misericordiae University Hospital, D07 R2WY Dublin, Ireland
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43
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Cao G, Ye M, Wang H, Liu Y, Li M. The Role of Biomechanical Forces in the Formation and Treatment of Pathological Scars. Clin Cosmet Investig Dermatol 2024; 17:2565-2571. [PMID: 39559183 PMCID: PMC11570529 DOI: 10.2147/ccid.s496253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/14/2024] [Accepted: 11/07/2024] [Indexed: 11/20/2024]
Abstract
Pathological scars, including hypertrophic scar and keloid are the result of excessive tissue repair and are influenced by biomechanical forces like tension, mechanical pressure, and stiffness. These forces significantly impact scar development and progression, affecting wound healing, collagen deposition, and tissue remodeling. Understanding how these mechanical stimuli contribute to scar development is essential for devising effective therapeutic interventions. Clinically, reducing wound tension and applying mechanical pressure are key strategies for managing pathological scars. Techniques like super-tension-reduction suturing, stress-shielding polymers, and force-modulating tissue bridges (FMTB) have been shown to effectively alleviate tension and reduce scar proliferation. Additionally, Pressure Garment Therapy (PGT) is widely used to treat hypertrophic scars by reducing tissue stiffness, limiting collagen buildup, and promoting collagen realignment. Despite challenges such as discomfort and uneven pressure application, ongoing research focuses on enhancing these therapies through mechanosensitive technologies to improve both efficacy and patient comfort. This review highlights the role of biomechanical forces in scar formation and discusses therapeutic approaches that target these forces to improve clinical outcomes.
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Affiliation(s)
- Guangtong Cao
- Department of Burns and Plastic Surgery & Wound Repair Surgery, Second Hospital of Lanzhou University, Lanzhou, Gansu, 730030People’s Republic of China
| | - Mingmin Ye
- Department of Plastic Surgery, Gansu Provincial Hospital, Lanzhou, Gansu, People’s Republic of China
| | - Haiyan Wang
- Department of Ultrasound Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
| | - Yi Liu
- Department of Burns and Plastic Surgery & Wound Repair Surgery, Second Hospital of Lanzhou University, Lanzhou, Gansu, 730030People’s Republic of China
| | - Mengzhi Li
- Department of Hand, Foot, and Microsurgical Reconstruction, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China
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Schoberleitner I, Faserl K, Lackner M, Coraça-Huber DC, Augustin A, Imsirovic A, Sigl S, Wolfram D. Unraveling the Immune Web: Advances in SMI Capsular Fibrosis from Molecular Insights to Preclinical Breakthroughs. Biomolecules 2024; 14:1433. [PMID: 39595609 PMCID: PMC11592141 DOI: 10.3390/biom14111433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/07/2024] [Revised: 11/06/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Breast implant surgery has evolved significantly, yet challenges such as capsular contracture remain a persistent concern. This review presents an in-depth analysis of recent advancements in understanding the immune mechanisms and clinical implications associated with silicone mammary implants (SMIs). The article systematically examines the complex interplay between immune responses and capsular fibrosis, emphasizing the pathophysiological mechanisms of inflammation in the etiology of this fibrotic response. It discusses innovations in biomaterial science, including the development of novel anti-biofilm coatings and immunomodulatory surfaces designed to enhance implant integration and minimize complications. Emphasis is placed on personalized risk assessment strategies, leveraging molecular insights to tailor interventions and improve patient outcomes. Emerging therapeutic targets, advancements in surgical techniques, and the refinement of post-operative care are also explored. Despite notable progress, challenges such as the variability in immune responses, the long-term efficacy of new interventions, and ethical considerations remain. Future research directions are identified, focusing on personalized medicine, advanced biomaterials, and bridging preclinical findings with clinical applications. As we advance from bench to bedside, this review illuminates the path forward, where interdisciplinary collaboration and continued inquiry weave together to enhance the art and science of breast implant surgery, transforming patient care into a realm of precision and excellence.
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Affiliation(s)
- Ines Schoberleitner
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Müllerstraße 44, 6020 Innsbruck, Austria
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Klaus Faserl
- Protein Core Facility, Institute of Medical Chemistry, Biocenter, Medical University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria
| | - Michaela Lackner
- Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Schöpfstraße 41, 6020 Innsbruck, Austria
| | - Débora C. Coraça-Huber
- BIOFILM Lab, Department of Orthopedics and Traumatology, Medical University of Innsbruck, Müllerstraße 44, 6020 Innsbruck, Austria
| | - Angela Augustin
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Anja Imsirovic
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Stephan Sigl
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
| | - Dolores Wolfram
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
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Zhao X, Fan Z, Zhou J, Li Y, Zhu W, Su S, Xia J. An alternative way to break the matrix barrier: an experimental study of a LIFU-mediated, visualizable targeted nanoparticle synergistic amplification for the treatment of malignant fibroblasts. Front Bioeng Biotechnol 2024; 12:1486369. [PMID: 39564102 PMCID: PMC11574418 DOI: 10.3389/fbioe.2024.1486369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/26/2024] [Accepted: 10/15/2024] [Indexed: 11/21/2024] Open
Abstract
Malignant fibroblasts (MFs) are widely present in various diseases and are characterized by connective tissue proliferation; these cells act as a physical barrier that severely limits drug delivery and affects disease outcomes. Based on this, we constructed the smart, integrated, theranostic, targeted lipid nanoprobe HMME-RG3@PFH to overcome the bottleneck in the early diagnosis and treatment of MF-related diseases. The protein glucose transporter protein 1 (GLUT-1) is overexpressed on MFs, and its ideal substrate, ginsenoside RG3 (RG3), significantly enhances the targeted uptake of HMME-RG3@PFH by MFs in a hypoxic environment and endows the nanomaterial with stealthiness to prolong its circulation. Perfluorohexane (PFH), a substance that can undergo phase change, was encapsulated in the lipid core and vaporized for ultrasound-enhanced imaging under low-intensity focused ultrasound (LIFU) irradiation. Moreover, hematoporphyrin monomethyl ether (HMME) was loaded into the lipid bilayer for photoacoustic molecular imaging and sonodynamic therapy (SDT) of MFs under the combined effects of LIFU. Additionally, HMME-RG3@PFH instantaneously burst during visualization to promote targeted drug delivery. In addition, the increased number of exposed RG3 fragments can regulate the MFs to enter a quiescent state. Overall, this nanoplatform ultimately achieves dual-modal imaging with targeted and precise drug release for visualization and synergistic amplification therapy, providing a new possibility for the early diagnosis and precise treatment of MF-related diseases.
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Affiliation(s)
- Xiangzhi Zhao
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Zhengchao Fan
- Department of Ultrasound, Sichuan Provincial Second Hospital of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Junan Zhou
- Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Ying Li
- Department of Plastic and Burns Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Weiwei Zhu
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Song Su
- Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jizhu Xia
- Department of Ultrasound, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Liao J, Li X, Yang H, He W, Wang B, Liu S, Fan Y. Construction of a Curcumin‐Loaded PLLA/PCL Micro‐Nano Conjugated Fibrous Membrane to Synergistically Prevent Postoperative Adhesion From Multiple Perspectives. ADVANCED FUNCTIONAL MATERIALS 2024; 34. [DOI: 10.1002/adfm.202407983] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 05/09/2024] [Indexed: 02/02/2025]
Abstract
AbstractPostoperative adhesion (POA) has emerged as a prevalent clinical challenge in soft tissue repair, emphasizing the critical need for preventive measures. However, the complex POA development process makes POA prevention from a single aspect insufficient. Hence, a curcumin‐loaded poly‐L‐lactic acid‐poly (caprolactone) micro‐nano conjugated fibrous membrane (PAPC MCFM (cur)) is engineered to synergistically prevent POA from multiple perspectives, in which poly (caprolactone) (PCL) nanofibers (118 ± 12 nm) with low orientation traverse the oriented poly‐L‐lactic acid (PLLA) microfibers (2.0 ± 0.3 µm). The PAPC MCFM not only significantly improves the mechanical properties of the anisotropic fibrous membrane (AIFM) that the modulus of elasticity and the tensile strength in the direction vertical to microfiber orientation increase by 4.5 and 13.0 times, respectively, but also can further enhance the “contact guidance effect” of AIFM, i.e., hindering fibroblast adhesion, proliferation, and differentiation to myofibroblast through inhibiting integrin β1 activation, vinculin expression and focal adhesion (FA) formation, and the nuclear localization activation of yes‐associated protein (YAP). Except for these effects, PAPC MCFM loading with 2.5 mg mL−1 curcumin can further prevent POA by delivering anti‐inflammatory, antioxidant, and antibacterial properties, and by suppressing fibrosis through decreased transforming growth factor‐β1(TGF‐β1) expression, showing effective POA prevention in rat abdominal cavity and rabbit dura mater models.
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Affiliation(s)
- Jie Liao
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education Beijing Advanced Innovation Center for Biomedical Engineering School of Biological Science and Medical Engineering Beihang University Beijing 100083 China
- Department of Biomedical Materials Science College of Biomedical Engineering Third Military Medical University Chongqing 400038 China
| | - Xiaoming Li
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education Beijing Advanced Innovation Center for Biomedical Engineering School of Biological Science and Medical Engineering Beihang University Beijing 100083 China
| | - Huiqi Yang
- Department of Hernia and Abdominal Wall Surgery Beijing Chao‐Yang Hospital Beijing 100043 China
| | - Wei He
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education Beijing Advanced Innovation Center for Biomedical Engineering School of Biological Science and Medical Engineering Beihang University Beijing 100083 China
| | - Bingbing Wang
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education Beijing Advanced Innovation Center for Biomedical Engineering School of Biological Science and Medical Engineering Beihang University Beijing 100083 China
| | - Shuyu Liu
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education Beijing Advanced Innovation Center for Biomedical Engineering School of Biological Science and Medical Engineering Beihang University Beijing 100083 China
| | - Yubo Fan
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education Beijing Advanced Innovation Center for Biomedical Engineering School of Biological Science and Medical Engineering Beihang University Beijing 100083 China
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Shoji M, Kanno E, Tanno H, Yamaguchi K, Ishi S, Takagi N, Kurosaka S, Sato K, Niiyama M, Ito A, Ishii K, Imai Y, Kawakami K, Tachi M. CARD9-Mediated Macrophage Responses and Collagen Fiber Capsule Formation Caused by Textured Breast Implants. Plast Reconstr Surg 2024; 154:906e-917e. [PMID: 37847583 DOI: 10.1097/prs.0000000000011152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/19/2023]
Abstract
BACKGROUND An increasing number of women are undergoing breast implantation for cosmetic purposes or for reconstructive purposes after breast excision. The surface morphology of the breast implant is a key factor associated with the induction of capsule contraction. The effect of surface morphology on the inflammatory response after implant insertion remains unclear, however. The authors conducted comparative analyses to determine the effect of the textured and smooth surface morphology of silicone sheets. METHODS Each type of silicone sheet was inserted into the subcutaneous pocket below the panniculus carnosus in C57BL/6 mice and mice with genetic disruption of CARD9 , Dectin-1 , Dectin-2 , or Mincle . The authors analyzed collagen fiber capsule thickness, histologic findings, and macrophage inflammatory response, including transforming growth factor (TGF)-β synthesis. RESULTS The authors found that textured surface morphology contributed to the formation of collagen fiber capsules and the accumulation of fibroblasts and myofibroblasts, and was accompanied by the accumulation of TGF-β-expressing macrophages and foreign-body giant cells. CARD9 deficiency attenuated collagen fiber capsule formation, macrophage responses, and TGF-β synthesis, although the responsible C-type lectin receptors remain to be clarified. CONCLUSION These results suggest that CARD9 may have a strong impact on silicone sheet morphology through the regulation of macrophage responses. CLINICAL RELEVANCE STATEMENT Silicone breast implants have been widely used for postmastectomy and cosmetic augmentation mammaplasty breast reconstruction. The authors sought to elucidate the surface morphology of the breast implant as one of the key factors associated with the formation of collagen fiber capsules. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, V.
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Affiliation(s)
- Miki Shoji
- From the Departments of Plastic and Reconstructive Surgery
| | | | | | | | - Sinyo Ishi
- From the Departments of Plastic and Reconstructive Surgery
| | - Naoyuki Takagi
- From the Departments of Plastic and Reconstructive Surgery
| | - Shiho Kurosaka
- From the Departments of Plastic and Reconstructive Surgery
| | - Ko Sato
- Medical Microbiology, Mycology and Immunology
| | | | - Akihiko Ito
- Graduate School of Environment and Information Sciences, Yokohama National University
| | - Keiko Ishii
- Medical Microbiology, Mycology and Immunology
| | | | - Kazuyoshi Kawakami
- Medical Microbiology, Mycology and Immunology
- Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine
| | - Masahiro Tachi
- From the Departments of Plastic and Reconstructive Surgery
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Abbas N, Bentele M, Waleczek FJG, Fuchs M, Just A, Pfanne A, Pich A, Linke S, Neumüller S, Stucki-Koch A, Jordan M, Perbellini F, Werlein C, Korte W, Ius F, Ruhparwar A, Weber N, Fiedler J, Thum T. Ex vivo modelling of cardiac injury identifies ferroptosis-related pathways as a potential therapeutic avenue for translational medicine. J Mol Cell Cardiol 2024; 196:125-140. [PMID: 39341589 PMCID: PMC7617241 DOI: 10.1016/j.yjmcc.2024.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 01/25/2024] [Revised: 09/13/2024] [Accepted: 09/22/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Heart failure (HF) is a burgeoning health problem worldwide. Often arising as a result of cardiac injury, HF has become a major cause of mortality with limited availability of effective treatments. Ferroptotic pathways, triggering an iron-dependent form of cell death, are known to be potential key players in heart disease. This form of cell death does not exhibit typical characteristics of programmed cell death, and is mediated by impaired iron metabolism and lipid peroxidation signalling. OBJECTIVES The aim of this study is to establish an ex-vivo model of myocardial injury in living myocardial slices (LMS) and to identify novel underlying mechanisms and potential therapeutic druggable target(s). METHODS AND RESULTS In this study, we employed LMS as an ex vivo model of cardiac injury to investigate underlying mechanisms and potential therapeutic targets. Cryoinjury was induced in adult rat LMS, resulting in 30 % tissue damage. Cryoinjured LMS demonstrated impaired contractile function, cardiomyocyte hypertrophy, inflammation, and cardiac fibrosis, closely resembling in vivo cardiac injury characteristics. Proteomic analysis revealed an enrichment of factors associated with ferroptosis in the injured LMS, suggesting a potential causative role. To test this hypothesis, we pharmacologically inhibited ferroptotic pathways using ferrostatin (Fer-1) in the cryoinjured rat LMS, resulting in attenuation of structural changes and repression of pro-fibrotic processes. Furthermore, LMS generated from failing human hearts were used as a model of chronic heart failure. In this model, Fer-1 treatment was observed to reduce the expression of ferroptotic genes, enhances contractile function and improves tissue viability. Blocking ferroptosis-associated pathways in human cardiac fibroblasts (HCFs) resulted in a downregulation of fibroblast activation genes, a decrease in fibroblast migration capacity, and a reduction in reactive oxygen species production. RNA sequencing analysis of Fer-1-treated human LMS implicated metallothioneins as a potential underlying mechanism for the inhibition of these pathways. This effect is possibly mediated through the replenishment of glutathione reserves. CONCLUSIONS Our findings highlight the potential of targeting ferroptosis-related pathways and metallothioneins as a promising strategy for the treatment of heart disease.
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Affiliation(s)
- Naisam Abbas
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany
| | - Marco Bentele
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany
| | - Florian J G Waleczek
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany
| | - Maximilian Fuchs
- Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany
| | - Annette Just
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Angelika Pfanne
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Andreas Pich
- Institute of Toxicology and Core Unit Proteomics, Hannover Medical School, Hannover, Germany
| | - Sophie Linke
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Susanne Neumüller
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Angelika Stucki-Koch
- Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany
| | - Maria Jordan
- Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany
| | - Filippo Perbellini
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | | | - Wilhelm Korte
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Fabio Ius
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Arjang Ruhparwar
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Natalie Weber
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Jan Fiedler
- Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.
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Starobova H, Alshammari A, Winkler IG, Vetter I. The role of the neuronal microenvironment in sensory function and pain pathophysiology. J Neurochem 2024; 168:3620-3643. [PMID: 36394416 DOI: 10.1111/jnc.15724] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/17/2022] [Revised: 11/10/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022]
Abstract
The high prevalence of pain and the at times low efficacy of current treatments represent a significant challenge to healthcare systems worldwide. Effective treatment strategies require consideration of the diverse pathophysiologies that underlie various pain conditions. Indeed, our understanding of the mechanisms contributing to aberrant sensory neuron function has advanced considerably. However, sensory neurons operate in a complex dynamic microenvironment that is controlled by multidirectional interactions of neurons with non-neuronal cells, including immune cells, neuronal accessory cells, fibroblasts, adipocytes, and keratinocytes. Each of these cells constitute and control the microenvironment in which neurons operate, inevitably influencing sensory function and the pathology of pain. This review highlights the importance of the neuronal microenvironment for sensory function and pain, focusing on cellular interactions in the skin, nerves, dorsal root ganglia, and spinal cord. We discuss the current understanding of the mechanisms by which neurons and non-neuronal cells communicate to promote or resolve pain, and how this knowledge could be used for the development of mechanism-based treatments.
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Affiliation(s)
- Hana Starobova
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia
| | - Ammar Alshammari
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia
| | - Ingrid G Winkler
- Mater Research Institute, The University of Queensland, Queensland, South Brisbane, Australia
| | - Irina Vetter
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia
- The School of Pharmacy, The University of Queensland, Woolloongabba, Queensland, Australia
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Spector I, Derech-Haim S, Boustanai I, Safrai M, Meirow D. Anti-Müllerian hormone signaling in the ovary involves stromal fibroblasts: a study in humans and mice provides novel insights into the role of ovarian stroma. Hum Reprod 2024; 39:2551-2564. [PMID: 39361580 DOI: 10.1093/humrep/deae221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/25/2024] [Revised: 07/08/2024] [Indexed: 10/05/2024] Open
Abstract
STUDY QUESTION What is the involvement of ovarian stroma in the anti-Müllerian hormone (AMH) signaling pathway and which stromal cells are involved? SUMMARY ANSWER Mouse and human ovaries show high expression of AMH receptor II (AMHR2) in the stromal fibroblasts surrounding the follicles and activation of the post-AMHR2 pathway by recombinant AMH was evidenced by increased phosphorylation of SMAD1,5 and 9, increased expression AMHR2 and upregulation of αSMA, suggesting fibroblast activation to initiate myofibroblast differentiation. WHAT IS KNOWN ALREADY AMH secreted by small growing follicles, regulates ovarian activity. It suppresses initial primordial follicle (PMF) recruitment and FSH-dependent growth. AMH signal transduction is mediated by AMHR2, activating intracellular SMAD proteins and other signaling cascades to induce target-gene expression. Although AMHR2 expression has been reported within the follicle unit, there is evidence suggesting it may be identified in the stroma as well. STUDY DESIGN, SIZE, DURATION Fresh murine ovaries were extracted from BALB/c mice (6 weeks old; n = 12 and 21 days old; n = 56). Frozen-thawed ovarian fragments were obtained from 10 women, aged 18-35, who had undergone ovarian tissue cryopreservation and donated frozen ovarian tissue for research. PARTICIPANTS/MATERIALS, SETTING, METHODS Murine (6 weeks old) and human donor ovaries were immunostained for AMHR2 and Collagen 1α/αSMA/VCAM1, with additional vimentin staining in mice. Murine (21 days old) and human donor ovaries were used for fibroblast isolation and subsequent 7-day cultures. Prior to assessing AMH effects on isolated fibroblast culture, purity validation tests were implemented to ensure the absence of epithelial, immune, endothel, granulosa, and theca ovarian cell populations. The fibroblast culture's homogeneity was validated by RT-qPCR and western-blot assays, confirming negativity for E-cadherin, CD31, aromatase, CYP17A1, and positivity for αSMA and vimentin. Fibroblasts were then subjected to rAMH treatment in vitro (200 ng/ml) for 0-72 h, with an additional time point of 96 h for human samples, followed by RT-qPCR, western blot, and immunocytochemistry (ICC) for AMHR2 expression. AMHR2 post-receptor signaling was examined by pSMAD1,5,9 levels via western blot. Activated fibroblast marker, αSMA, was assessed via western blot and ICC. MAIN RESULTS AND THE ROLE OF CHANCE Immunostaining of mouse and human ovarian tissue showed that stromal cells around follicles at all developmental stages exhibit high AMHR2 expression, while granulosa cells of growing follicles show considerably lower levels. The majority of these AMHR2-positive stromal cells were identified as fibroblasts (Collagen1α in mice and human; vimentin in mice). RT-qPCR, western blot, and immunostaining were performed on cultured mouse and human fibroblasts, confirming that they consisted of a pure fibroblast population (αSMA/vimentin positive and negative for other cell-type markers). A total of 99.81% (average 28.94 ± 1.34 cells/field in mice) and 100% (average 19.20 ± 1.39 cells/field in human samples) of these fibroblasts expressed AMHR2 (ICC). rAMH treated cultured fibroblasts showed increased pSMAD1,5 and 9 levels, demonstrating the effects of AMH on its downstream signaling pathway. pSMAD1,5 and 9 expression increased, as detected by western blot: 1.92-fold in mice (48 h, P = 0.026) and 2.37-fold in human samples (48 h, P = 0.0002). In addition, rAMH treatment increased AMHR2 protein expression, as observed in ICC (human): a 2.57-fold upregulation of AMHR2 Mean Fluorescence Intensity (MFI) (96 h, P = 0.00036), and western blot, showing a 4.2-fold time-dependent increase (48 h, P = 0.026) in mice and 2.4-fold change (48 h, P = 0.0003) in human donors. Exposure to rAMH affected AMHR2 transcription upregulation, with a 6.48-fold change (72 h, P = 0.0137) in mice and a 7.87-fold change (72 h, P < 0.0001) in humans. rAMH treatment induced fibroblast activation (αSMA positive), demonstrating the dynamic effects of AMH on fibroblast behavior. αSMA expression elevation was detected in ICC with a 2.28-fold MFI increase in humans (96 h, P = 0.000067), and in western blot with a 5.12-fold increase in mice (48 h, P = 0.0345) and a 2.69-fold increase in humans (48 h, P ≤ 0.0001). Activated AMHR2-positive stained fibroblast fractions were solely located around growing follicles, in both human and mice. In addition, a small population of AMHR2-positive stained theca cells (VCAM1 positive) was observed. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Ex vivo, fibroblast gene expression might be changed by adhesion to the tissue-culture plate. Nevertheless, cultured fibroblasts (with and without rAMH) are subjected to the same conditions. Observations or significant differences can therefore be considered reliable. In addition, the presented effect of rAMH on fibroblasts is not directly linked to the known inhibitory effect of AMH on follicle activation. WIDER IMPLICATIONS OF THE FINDINGS Clarifying the populations of AMH-responsive cells in the ovary provides a foundation for further investigation of the complex AMH signaling across the ovary. The composition of AMH-releasing and -responsive cells can shed light on the communication network between follicles and their environment, which may elucidate the mechanisms behind the AMH inhibitory effect on PMF activation. STUDY FUNDING/COMPETING INTEREST(S) This work was financially supported by grants from the Kahn Foundation. There are no competing interests in this study. TRIAL REGISTRATION NUMBER N/A.
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Affiliation(s)
- Itay Spector
- Fertility Preservation Laboratory, Sheba Medical Center, Tel Hashomer, Israel
| | - Sanaz Derech-Haim
- Fertility Preservation Laboratory, Sheba Medical Center, Tel Hashomer, Israel
- Faculty of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ilana Boustanai
- Fertility Preservation Laboratory, Sheba Medical Center, Tel Hashomer, Israel
| | - Myriam Safrai
- Fertility Preservation Laboratory, Sheba Medical Center, Tel Hashomer, Israel
| | - Dror Meirow
- Fertility Preservation Laboratory, Sheba Medical Center, Tel Hashomer, Israel
- Faculty of Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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