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Zhou W, Wang J, Ding L, Cai R, Cheng J, Liang P, Zhu Y, Zhang Z. Autophagy inhibition enhances antifibrotic potential of placental mesenchymal stem cells of fetal origin via regulating TGF-β1 mediated protein degradation of HGF. Sci Rep 2025; 15:13805. [PMID: 40258831 PMCID: PMC12012010 DOI: 10.1038/s41598-025-97054-8] [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] [Scholar Register] [Received: 12/22/2024] [Accepted: 04/02/2025] [Indexed: 04/23/2025] Open
Abstract
Mesenchymal stem cell (MSC) therapy represents a promising strategy for pulmonary fibrosis (PF) treatment, with hepatocyte growth factor (HGF) serving as a key mediator of MSC-mediated protection. However, the therapeutic efficacy of MSCs is limited by the complex PF microenvironment, and the mechanisms underlying this limitation remain unclear. This study investigates how the PF pathological microenvironment modulates the antifibrotic potential of placental mesenchymal stem cells of fetal origin (fPMSCs) through HGF regulation and elucidates the molecular mechanisms involved. Morphological analysis, flow cytometry, and multilineage differentiation assays were employed to characterize fPMSCs. Transforming growth factor-β1 (TGF-β1) was employed to simulate the PF microenvironment and activate fPMSCs in vitro. ELISA and Western blotting were used to analyze HGF expression, autophagy markers, and Smad signaling. Autophagosome formation was visualized via confocal microscopy and transmission electron microscopy. Co-immunoprecipitation (Co-IP) assays were performed to assess the interaction between p62 and HGF. The antifibrotic function of fPMSCs was further evaluated using a transwell co-culture system with MRC-5 fibroblasts in vitro and a bleomycin-induced PF mouse model in vivo. Phenotypic characterization confirmed that fPMSCs exhibited canonical MSC morphology, expressed CD73/CD90/CD105, lacked CD14/CD34/CD45/HLA-DR, and differentiated into adipogenic, osteogenic, and chondrogenic lineages. TGF-β1 treatment robustly downregulated the antifibrotic capacity, HGF protein expression, and paracrine secretion in fPMSCs. Recombinant HGF enhanced antifibrotic effects, while an HGF-neutralizing antibody abolished them. TGF-β1 induced autophagy in fPMSCs, promoting HGF degradation via p62 interaction and impairing antifibrotic function in vitro and in vivo. Mechanistically, Smad3 phosphorylation mediated the regulation of autophagy and HGF expression in TGF-β1-treated fPMSCs. Our findings demonstrate that TGF-β1 impairs the antifibrotic function of fPMSCs via autophagy-dependent HGF degradation and Smad3 signaling. Conversely, autophagy inhibition restores HGF levels and enhances fPMSCs' therapeutic efficacy in a preclinical PF model. Targeting autophagy inhibition emerges as a promising therapeutic strategy to counteract pulmonary fibrosis.
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Affiliation(s)
- Wei Zhou
- The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750000, Ningxia, China
- The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750000, Ningxia, China
| | - Jing Wang
- The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750000, Ningxia, China
| | - Lu Ding
- School of Basic Medicine, Ningxia Medical University, Yinchuan, 750000, Ningxia, China
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, 804 W. Shengli Road, Yinchuan, 750000, Ningxia, China
| | - Ruizhi Cai
- The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750000, Ningxia, China
| | - Jie Cheng
- The Third School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750000, Ningxia, China
| | - Panpan Liang
- The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750000, Ningxia, China
| | - Yongzhao Zhu
- Institute of Medical Sciences, General Hospital of Ningxia Medical University, 804 W. Shengli Road, Yinchuan, 750000, Ningxia, China.
| | - Zaiqi Zhang
- The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750000, Ningxia, China.
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Mamun AA, Shao C, Geng P, Wang S, Xiao J. Recent advances in molecular mechanisms of skin wound healing and its treatments. Front Immunol 2024; 15:1395479. [PMID: 38835782 PMCID: PMC11148235 DOI: 10.3389/fimmu.2024.1395479] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/03/2024] [Indexed: 06/06/2024] Open
Abstract
The skin, being a multifaceted organ, performs a pivotal function in the complicated wound-healing procedure, which encompasses the triggering of several cellular entities and signaling cascades. Aberrations in the typical healing process of wounds may result in atypical scar development and the establishment of a persistent condition, rendering patients more vulnerable to infections. Chronic burns and wounds have a detrimental effect on the overall quality of life of patients, resulting in higher levels of physical discomfort and socio-economic complexities. The occurrence and frequency of prolonged wounds are on the rise as a result of aging people, hence contributing to escalated expenditures within the healthcare system. The clinical evaluation and treatment of chronic wounds continue to pose challenges despite the advancement of different therapeutic approaches. This is mainly owing to the prolonged treatment duration and intricate processes involved in wound healing. Many conventional methods, such as the administration of growth factors, the use of wound dressings, and the application of skin grafts, are used to ease the process of wound healing across diverse wound types. Nevertheless, these therapeutic approaches may only be practical for some wounds, highlighting the need to advance alternative treatment modalities. Novel wound care technologies, such as nanotherapeutics, stem cell treatment, and 3D bioprinting, aim to improve therapeutic efficacy, prioritize skin regeneration, and minimize adverse effects. This review provides an updated overview of recent advancements in chronic wound healing and therapeutic management using innovative approaches.
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Affiliation(s)
- Abdullah Al Mamun
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
| | - Chuxiao Shao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
| | - Peiwu Geng
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
| | - Shuanghu Wang
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
| | - Jian Xiao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Jahanbani F, Sing JC, Maynard RD, Jahanbani S, Dafoe J, Dafoe W, Jones N, Wallace KJ, Rastan A, Maecker HT, Röst HL, Snyder MP, Davis RW. Longitudinal cytokine and multi-modal health data of an extremely severe ME/CFS patient with HSD reveals insights into immunopathology, and disease severity. Front Immunol 2024; 15:1369295. [PMID: 38650940 PMCID: PMC11033372 DOI: 10.3389/fimmu.2024.1369295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 03/18/2024] [Indexed: 04/25/2024] Open
Abstract
Introduction Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents substantial challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. The heterogeneity among patient populations, coupled with the absence of FDA-approved diagnostics and therapeutics, further complicates research into disease etiology and patient managment. Integrating longitudinal multi-omics data with clinical, health,textual, pharmaceutical, and nutraceutical data offers a promising avenue to address these complexities, aiding in the identification of underlying causes and providing insights into effective therapeutics and diagnostic strategies. Methods This study focused on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) during a period of marginal symptom improvements. Longitudinal cytokine profiling was conducted alongside the collection of extensive multi-modal health data to explore the dynamic nature of symptoms, severity, triggers, and modifying factors. Additionally, an updated severity assessment platform and two applications, ME-CFSTrackerApp and LexiTime, were introduced to facilitate real-time symptom tracking and enhance patient-physician/researcher communication, and evaluate response to medical intervention. Results Longitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy. Additionally, the data identified potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasized the importance of investigating adverse reactions to medication and supplements and drug interactions in ME/CFS severity and progression. Discussion Our study advocates for the integration of longitudinal multi-omics with multi-modal health data and artificial intelligence (AI) techniques to better understand ME/CFS and its major comorbidities. These findings highlight the significance of dysregulated Th2-type cytokines in patient stratification and precision medicine strategies. Additionally, our results suggest exploring the use of low-dose drugs with partial agonist activity as a potential avenue for ME/CFS treatment. This comprehensive approach emphasizes the importance of adopting a patient-centered care approach to improve ME/CFS healthcare management, disease severity assessment, and personalized medicine. Overall, these findings contribute to our understanding of ME/CFS and offer avenues for future research and clinical practice.
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Affiliation(s)
- Fereshteh Jahanbani
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Justin Cyril Sing
- Department of Molecular Genetics, Donnelly Center, University of Toronto, Toronto, ON, Canada
| | - Rajan Douglas Maynard
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Shaghayegh Jahanbani
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Veterans Affairs (VA) Palo Alto Health Care System, Palo Alto, CA, United States
| | - Janet Dafoe
- ME/CFS Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Whitney Dafoe
- ME/CFS Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Nathan Jones
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Kelvin J. Wallace
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Azuravesta Rastan
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Holden T. Maecker
- Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Pulmonary and Critical Care Medicine, Institute of Immunity, Transplantation, and Infectious Diseases, Stanford University, Palo Alto, CA, United States
| | - Hannes L. Röst
- Department of Molecular Genetics, Donnelly Center, University of Toronto, Toronto, ON, Canada
| | - Michael P. Snyder
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
| | - Ronald W. Davis
- ME/CFS Collaborative Research Center at Stanford, Stanford Genome Technology Center, Stanford University School of Medicine, Palo Alto, CA, United States
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Jakl V, Popp T, Haupt J, Port M, Roesler R, Wiese S, Friemert B, Rojewski MT, Schrezenmeier H. Effect of Expansion Media on Functional Characteristics of Bone Marrow-Derived Mesenchymal Stromal Cells. Cells 2023; 12:2105. [PMID: 37626914 PMCID: PMC10453497 DOI: 10.3390/cells12162105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The therapeutic efficacy of mesenchymal stromal cells (MSCs) has been shown to rely on their immunomodulatory and regenerative properties. In order to obtain sufficient numbers of cells for clinical applications, MSCs have to be expanded ex vivo. Expansion media with xenogeneic-free (XF) growth-promoting supplements like human platelet lysate (PL) or serum- and xenogeneic-free (SF/XF) formulations have been established as safe and efficient, and both groups provide different beneficial qualities. In this study, MSCs were expanded in XF or SF/XF media as well as in mixtures thereof. MSCs cultured in these media were analyzed for phenotypic and functional properties. MSC expansion was optimal with SF/XF conditions when PL was present. Metabolic patterns, consumption of growth factors, and secretome of MSCs differed depending on the type and concentration of supplement. The lactate per glucose yield increased along with a higher proportion of PL. Many factors in the supernatant of cultured MSCs showed distinct patterns depending on the supplement (e.g., FGF-2, TGFβ, and insulin only in PL-expanded MSC, and leptin, sCD40L PDGF-AA only in SF/XF-expanded MSC). This also resulted in changes in cell characteristics like migratory potential. These findings support current approaches where growth media may be utilized for priming MSCs for specific therapeutic applications.
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Affiliation(s)
- Viktoria Jakl
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
| | - Tanja Popp
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Julian Haupt
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Matthias Port
- Bundeswehr Institute of Radiobiology, 80937 Munich, Germany (J.H.); (M.P.)
| | - Reinhild Roesler
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Sebastian Wiese
- Core Unit of Mass Spectrometry and Proteomics, Ulm University Medical Center, 89081 Ulm, Germany; (R.R.); (S.W.)
| | - Benedikt Friemert
- Clinic for Trauma Surgery and Orthopedics, Army Hospital Ulm, 89081 Ulm, Germany
| | - Markus T. Rojewski
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
| | - Hubert Schrezenmeier
- Institute for Transfusion Medicine, University Hospital Ulm, 89081 Ulm, Germany; (V.J.)
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Donation Service Baden-Württemberg—Hessia and University Hospital Ulm, 89081 Ulm, Germany
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Zhou H, He Y, Xiong W, Jing S, Duan X, Huang Z, Nahal GS, Peng Y, Li M, Zhu Y, Ye Q. MSC based gene delivery methods and strategies improve the therapeutic efficacy of neurological diseases. Bioact Mater 2023; 23:409-437. [PMCID: PMC9713256 DOI: 10.1016/j.bioactmat.2022.11.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/08/2022] [Accepted: 11/13/2022] [Indexed: 12/05/2022] Open
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Molecular Mechanisms Responsible for Mesenchymal Stem Cell-Based Modulation of Obstructive Sleep Apnea. Int J Mol Sci 2023; 24:ijms24043708. [PMID: 36835120 PMCID: PMC9958695 DOI: 10.3390/ijms24043708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/16/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells that reside in almost all postnatal tissues where, due to the potent regenerative, pro-angiogenic and immunomodulatory properties, regulate tissue homeostasis. Obstructive sleep apnea (OSA) induces oxidative stress, inflammation and ischemia which recruit MSCs from their niches in inflamed and injured tissues. Through the activity of MSC-sourced anti-inflammatory and pro-angiogenic factors, MSCs reduce hypoxia, suppress inflammation, prevent fibrosis and enhance regeneration of damaged cells in OSA-injured tissues. The results obtained in large number of animal studies demonstrated therapeutic efficacy of MSCs in the attenuation of OSA-induced tissue injury and inflammation. Herewith, in this review article, we emphasized molecular mechanisms which are involved in MSC-based neo-vascularization and immunoregulation and we summarized current knowledge about MSC-dependent modulation of OSA-related pathologies.
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Innovative Treatment Strategies to Accelerate Wound Healing: Trajectory and Recent Advancements. Cells 2022; 11:cells11152439. [PMID: 35954282 PMCID: PMC9367945 DOI: 10.3390/cells11152439] [Citation(s) in RCA: 164] [Impact Index Per Article: 54.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 11/26/2022] Open
Abstract
Wound healing is highly specialized dynamic multiple phase process for the repair of damaged/injured tissues through an intricate mechanism. Any failure in the normal wound healing process results in abnormal scar formation, and chronic state which is more susceptible to infections. Chronic wounds affect patients’ quality of life along with increased morbidity and mortality and are huge financial burden to healthcare systems worldwide, and thus requires specialized biomedical intensive treatment for its management. The clinical assessment and management of chronic wounds remains challenging despite the development of various therapeutic regimens owing to its painstakingly long-term treatment requirement and complex wound healing mechanism. Various conventional approaches such as cell therapy, gene therapy, growth factor delivery, wound dressings, and skin grafts etc., are being utilized for promoting wound healing in different types of wounds. However, all these abovementioned therapies are not satisfactory for all wound types, therefore, there is an urgent demand for the development of competitive therapies. Therefore, there is a pertinent requirement to develop newer and innovative treatment modalities for multipart therapeutic regimens for chronic wounds. Recent developments in advanced wound care technology includes nanotherapeutics, stem cells therapy, bioengineered skin grafts, and 3D bioprinting-based strategies for improving therapeutic outcomes with a focus on skin regeneration with minimal side effects. The main objective of this review is to provide an updated overview of progress in therapeutic options in chronic wounds healing and management over the years using next generation innovative approaches. Herein, we have discussed the skin function and anatomy, wounds and wound healing processes, followed by conventional treatment modalities for wound healing and skin regeneration. Furthermore, various emerging and innovative strategies for promoting quality wound healing such as nanotherapeutics, stem cells therapy, 3D bioprinted skin, extracellular matrix-based approaches, platelet-rich plasma-based approaches, and cold plasma treatment therapy have been discussed with their benefits and shortcomings. Finally, challenges of these innovative strategies are reviewed with a note on future prospects.
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Meng HF, Jin J, Wang H, Wang LS, Wu CT. Recent advances in the therapeutic efficacy of hepatocyte growth factor gene-modified mesenchymal stem cells in multiple disease settings. J Cell Mol Med 2022; 26:4745-4755. [PMID: 35922965 PMCID: PMC9465188 DOI: 10.1111/jcmm.17497] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/16/2022] [Accepted: 07/08/2022] [Indexed: 11/30/2022] Open
Abstract
Mesenchymal stem cell (MSC) therapy is considered a new treatment for a wide range of diseases and injuries, but challenges remain, such as poor survival, homing and engraftment rates, thus limiting the therapeutic efficacy of the transplanted MSCs. Many strategies have been developed to enhance the therapeutic efficacy of MSCs, such as preconditioning, co-transplantation with graft materials and gene modification. Hepatocyte growth factor (HGF) is secreted by MSCs, which plays an important role in MSC therapy. It has been reported that the modification of the HGF gene is beneficial to the therapeutic efficacy of MSCs, including diseases of the heart, lung, liver, urinary system, bone and skin, lower limb ischaemia and immune-related diseases. This review focused on studies involving HGF/MSCs both in vitro and in vivo. The characteristics of HGF/MSCs were summarized, and the mechanisms of their improved therapeutic efficacy were analysed. Furthermore, some insights are provided for HGF/MSCs' clinical application based on our understanding of the HGF gene and MSC therapy.
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Affiliation(s)
- Hong-Fang Meng
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Jide Jin
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Hua Wang
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Li-Sheng Wang
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Chu-Tse Wu
- School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China
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Zhang HZ, Han S, Kim S. SDF-1-edited human amniotic mesenchymal stem cells stimulate angiogenesis in treating hindlimb ischaemia. J Cell Mol Med 2022; 26:3726-3735. [PMID: 35615995 PMCID: PMC9258703 DOI: 10.1111/jcmm.17401] [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] [Scholar Register] [Received: 11/17/2021] [Revised: 04/15/2022] [Accepted: 05/08/2022] [Indexed: 11/29/2022] Open
Abstract
Although stem cells have extensively been studied as a novel vehicle for tissue repair, their sustained efficacy remains controversial. In this study, we aimed to investigate the angiogenic potency over time of stromal cell-derived factor-1 (SDF-1) gene-edited amniotic mesenchymal stem cells (AMM/S) in a hindlimb ischaemia model. An SDF-1 transgene was inserted into the AMM cell genome via transcription activator-like effector nuclease (TALEN) mediated knock-in, and cell migration, Matrigel tube formation, and in vivo Matrigel plug assays were performed. AMM/S were also transplanted into hindlimb ischaemia model mice. Blood perfusion, therapeutic potential, histology, capillary density and in vivo angiogenic assays were performed. AMM/S exhibited high expression of the SDF-1 gene, and robustly promoted migration, proliferation and microvascular formation. AMM/S transplantation significantly increased blood perfusion and limb loss prevention compared with AMM. AMM/S also significantly inhibited increased capillary density and expression of angiogenic factors in the ischaemic hindlimb. Our study demonstrated that AMM/S provides a significant therapeutic effect in ischaemic hindlimbs by enhancing angiogenesis.
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Affiliation(s)
- Hong Zhe Zhang
- Department of CardiologyThe Seventh Affiliated Hospital of Southern Medical UniversityFoshanChina
| | - Seongho Han
- Department of Family MedicineCollege of Medicine, Dong‐A UniversityBusanKorea
| | - Sung‐Whan Kim
- Institute for Bio‐Medical Convergence, Department MedicineCollege of Medicine, Catholic Kwandong UniversityGangneungKorea
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Gong T, Wu M, Fan X, Chen Z, Xia Z. Lentivirus-mediated subcutaneous JAM-A modification promotes skin wound healing in a mouse model by strengthening the secretory function and proliferation of fibroblasts. Cell Biol Int 2022; 46:1227-1235. [PMID: 35419903 DOI: 10.1002/cbin.11808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/28/2022] [Accepted: 03/24/2022] [Indexed: 11/07/2022]
Abstract
A better understanding of the molecular regulation of wound healing may provide novel therapeutic targets. A previous study revealed that junctional adhesion molecule A (JAM-A)-modified mesenchymal stem cells promoted wound healing. However, whether direct JAM-A modification in the skin wound edge area accelerates the wound repair process is not clear. We determined whether JAM-A modification at the skin wound edge accelerated the wound healing process. We established JAM-A modification mouse wound models and mouse primary fibroblast cell models. Wound pictures were taken to compare the wound size. H&E staining was performed to monitor the morphology of the wound and quality of the newborn skin. CCK-8 assays and immunofluorescence (IF) for Ki67 were used to measure the cell proliferation of mouse primary fibroblasts. Quantitative real-time PCR, immunohistochemistry, IF, and Western blot analysis were used to detect bFGF and EGF expression in vivo and in vitro. The JAM-A-overexpressing group exhibited a smaller residual wound size than the control group at Day 7. Thicker epidermal layers and more hair follicle-like structures were found in the JAM-A-overexpressing group at Day 21. Cell proliferation capacity was higher in JAM-A-modified mouse fibroblasts. Elevated levels of bFGF and EGF were found in the JAM-A-modified group in vivo and in vitro. JAM-A modification significantly promoted fibroblast proliferation and wound healing. Increased levels of bFGF and EGF growth factors may be part of the mechanism.
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Affiliation(s)
- Teng Gong
- Departments of Burn and Wound Repair, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Burn Institute, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Burn Medical Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Provincial Key Laboratory of Burn and Trauma, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Minjuan Wu
- Department of Histology and Embryology, Naval Medical University, Shanghai, China
| | - Xiaoming Fan
- Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, China.,Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Zhaohong Chen
- Departments of Burn and Wound Repair, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Burn Institute, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Burn Medical Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Provincial Key Laboratory of Burn and Trauma, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Zhaofan Xia
- Departments of Burn and Wound Repair, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Burn Institute, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Burn Medical Center, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Fujian Provincial Key Laboratory of Burn and Trauma, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.,Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, China.,Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
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Soltanyzadeh M, Khorsand B, Baneh AA, Houri H. Clarifying differences in gene expression profile of umbilical cord vein and bone marrow-derived mesenchymal stem cells; a comparative in silico study. INFORMATICS IN MEDICINE UNLOCKED 2022. [DOI: 10.1016/j.imu.2022.101072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
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12
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Gardin C, Ferroni L, Erdoğan YK, Zanotti F, De Francesco F, Trentini M, Brunello G, Ercan B, Zavan B. Nanostructured Modifications of Titanium Surfaces Improve Vascular Regenerative Properties of Exosomes Derived from Mesenchymal Stem Cells: Preliminary In Vitro Results. NANOMATERIALS 2021; 11:nano11123452. [PMID: 34947800 PMCID: PMC8707709 DOI: 10.3390/nano11123452] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/05/2021] [Accepted: 12/09/2021] [Indexed: 01/02/2023]
Abstract
(1) Background: Implantation of metal-based scaffolds is a common procedure for treating several diseases. However, the success of the long-term application is limited by an insufficient endothelialization of the material surface. Nanostructured modifications of metal scaffolds represent a promising approach to faster biomaterial osteointegration through increasing of endothelial commitment of the mesenchymal stem cells (MSC). (2) Methods: Three different nanotubular Ti surfaces (TNs manufactured by electrochemical anodization with diameters of 25, 80, or 140 nm) were seeded with human MSCs (hMSCs) and their exosomes were isolated and tested with human umbilical vein endothelial cells (HUVECs) to assess whether TNs can influence the secretory functions of hMSCs and whether these in turn affect endothelial and osteogenic cell activities in vitro. (3) Results: The hMSCs adhered on all TNs and significantly expressed angiogenic-related factors after 7 days of culture when compared to untreated Ti substrates. Nanomodifications of Ti surfaces significantly improved the release of hMSCs exosomes, having dimensions below 100 nm and expressing CD63 and CD81 surface markers. These hMSC-derived exosomes were efficiently internalized by HUVECs, promoting their migration and differentiation. In addition, they selectively released a panel of miRNAs directly or indirectly related to angiogenesis. (4) Conclusions: Preconditioning of hMSCs on TNs induced elevated exosomes secretion that stimulated in vitro endothelial and cell activity, which might improve in vivo angiogenesis, supporting faster scaffold integration.
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Affiliation(s)
- Chiara Gardin
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy; (C.G.); (L.F.)
| | - Letizia Ferroni
- Maria Cecilia Hospital, GVM Care & Research, Cotignola, 48033 Ravenna, Italy; (C.G.); (L.F.)
| | - Yaşar Kemal Erdoğan
- Biomedical Engineering Program, Middle East Technical University, Ankara 06800, Turkey; (Y.K.E.); (B.E.)
- Department of Biomedical Engineering, Isparta University of Applied Science, Isparta 32260, Turkey
| | - Federica Zanotti
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.Z.); (M.T.)
| | - Francesco De Francesco
- Department of Plastic and Reconstructive Surgery-Hand Surgery Unit, Azienda ‘Ospedali Riuniti’, 60126 Ancona, Italy;
| | - Martina Trentini
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.Z.); (M.T.)
| | - Giulia Brunello
- Department of Neurosciences, Dentistry Section, University of Padova, 35128 Padova, Italy;
- Department of Oral Surgery, University Clinic Düsseldorf, 40225 Dusseldorf, Germany
| | - Batur Ercan
- Biomedical Engineering Program, Middle East Technical University, Ankara 06800, Turkey; (Y.K.E.); (B.E.)
- Department of Metallurgical and Materials Engineering, Middle East Technical University, Ankara 06800, Turkey
- BIOMATEN, METU Center of Excellence in Biomaterials and Tissue Engineering, Ankara 06800, Turkey
| | - Barbara Zavan
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (F.Z.); (M.T.)
- Correspondence: ; Tel.: +39-0532455502
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13
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Bone marrow-derived mesenchymal stem cells transplantation attenuates renal fibrosis following acute kidney injury by repairing the peritubular capillaries. Exp Cell Res 2021; 411:112983. [PMID: 34921827 DOI: 10.1016/j.yexcr.2021.112983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 12/09/2021] [Accepted: 12/14/2021] [Indexed: 11/23/2022]
Abstract
After the severe initial insults of acute kidney injury, progressive kidney tubulointerstitial fibrosis may occur, the peritubular capillary (PTC) rarefaction plays a key role in the disease progression. However, the mechanisms of PTC damage were not fully understood and potential therapeutic interventions were not explored. Previous studies of our research team and others in this field suggested that bone marrow-derived mesenchymal stem cells (BMSCs) transplanted into the AKI rat model may preserve the kidney function and pathological changes. In the current study, with the ischemia/reperfusion AKI rat model, we revealed that BMSCs transplantation attenuated the renal function decrease in the AKI model through preserving the peritubular capillaries (PTCs) function. The density of PTCs is maintained by BMSCs transplantation in the AKI model, detachment and relocation of pericytes in the PTCs diminished. Then we established that BMSCs transplantation may attenuate the renal fibrosis and preserve the kidney function after AKI by repairing the PTCs. Improving the vitality of pericytes, suppressing the detachment and trans-differentiation of pericytes, directly differentiation of BMSCs into pericytes by BMSCs transplantation all participate in the PTC repair. Through these processes, BMSCs rescued the microvascular damage and improved the density of PTCs. As a result, a preliminary conclusion can be reached that BMSCs transplantation can be an effective therapy for delaying renal fibrosis after AKI.
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14
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Cho HM, Cho JY. Cardiomyocyte Death and Genome-Edited Stem Cell Therapy for Ischemic Heart Disease. Stem Cell Rev Rep 2021; 17:1264-1279. [PMID: 33492627 PMCID: PMC8316208 DOI: 10.1007/s12015-020-10096-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2020] [Indexed: 01/14/2023]
Abstract
Massive death of cardiomyocytes is a major feature of cardiovascular diseases. Since the regenerative capacity of cardiomyocytes is limited, the regulation of their death has been receiving great attention. The cell death of cardiomyocytes is a complex mechanism that has not yet been clarified, and it is known to appear in various forms such as apoptosis, necrosis, etc. In ischemic heart disease, the apoptosis and necrosis of cardiomyocytes appear in two types of programmed forms (intrinsic and extrinsic pathways) and they account for a large portion of cell death. To repair damaged cardiomyocytes, diverse stem cell therapies have been attempted. However, despite the many positive effects, the low engraftment and survival rates have clearly limited the application of stem cells in clinical therapy. To solve these challenges, the introduction of the desired genes in stem cells can be used to enhance their capacity and improve their therapeutic efficiency. Moreover, as genome engineering technologies have advanced significantly, safer and more stable delivery of target genes and more accurate deletion of genes have become possible, which facilitates the genetic modification of stem cells. Accordingly, stem cell therapy for damaged cardiac tissue is expected to further improve. This review describes myocardial cell death, stem cell therapy for cardiac repair, and genome-editing technologies. In addition, we introduce recent stem cell therapies that incorporate genome-editing technologies in the myocardial infarction model. Graphical Abstract.
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Affiliation(s)
- Hyun-Min Cho
- Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Gwanak-ro1, Gwanak-gu, Seoul, 151-742, South Korea
| | - Je-Yoel Cho
- Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Gwanak-ro1, Gwanak-gu, Seoul, 151-742, South Korea.
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15
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Drzeniek NM, Mazzocchi A, Schlickeiser S, Forsythe SD, Moll G, Geißler S, Reinke P, Gossen M, Gorantla VS, Volk HD, Soker S. Bio-instructive hydrogel expands the paracrine potency of mesenchymal stem cells. Biofabrication 2021; 13:10.1088/1758-5090/ac0a32. [PMID: 34111862 PMCID: PMC10024818 DOI: 10.1088/1758-5090/ac0a32] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/10/2021] [Indexed: 02/03/2023]
Abstract
The therapeutic efficacy of clinically applied mesenchymal stromal cells (MSCs) is limited due to their injection into harshin vivoenvironments, resulting in the significant loss of their secretory function upon transplantation. A potential strategy for preserving their full therapeutic potential is encapsulation of MSCs in a specialized protective microenvironment, for example hydrogels. However, commonly used injectable hydrogels for cell delivery fail to provide the bio-instructive cues needed to sustain and stimulate cellular therapeutic functions. Here we introduce a customizable collagen I-hyaluronic acid (COL-HA)-based hydrogel platform for the encapsulation of MSCs. Cells encapsulated within COL-HA showed a significant expansion of their secretory profile compared to MSCs cultured in standard (2D) cell culture dishes or encapsulated in other hydrogels. Functionalization of the COL-HA backbone with thiol-modified glycoproteins such as laminin led to further changes in the paracrine profile of MSCs. In depth profiling of more than 250 proteins revealed an expanded secretion profile of proangiogenic, neuroprotective and immunomodulatory paracrine factors in COL-HA-encapsulated MSCs with a predicted augmented pro-angiogenic potential. This was confirmed by increased capillary network formation of endothelial cells stimulated by conditioned media from COL-HA-encapsulated MSCs. Our findings suggest that encapsulation of therapeutic cells in a protective COL-HA hydrogel layer provides the necessary bio-instructive cues to maintain and direct their therapeutic potential. Our customizable hydrogel combines bioactivity and clinically applicable properties such as injectability, on-demand polymerization and tissue-specific elasticity, all features that will support and improve the ability to successfully deliver functional MSCs into patients.
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Affiliation(s)
- Norman M Drzeniek
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.,Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Andrea Mazzocchi
- Known Medicine Inc., 675 Arapeen Dr, Suite 103A-1, Salt Lake City, UT 84108, United States of America.,Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States of America
| | - Stephan Schlickeiser
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany
| | - Steven D Forsythe
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States of America
| | - Guido Moll
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.,Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Sven Geißler
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.,Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.,Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Manfred Gossen
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.,Institute of Active Polymers, Helmholtz-Zentrum Hereon, Kantstr. 55, Teltow 14513, Germany
| | - Vijay S Gorantla
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States of America
| | - Hans-Dieter Volk
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany
| | - Shay Soker
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States of America
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16
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Lopez-Mendez TB, Santos-Vizcaino E, Pedraz JL, Orive G, Hernandez RM. Cell microencapsulation technologies for sustained drug delivery: Latest advances in efficacy and biosafety. J Control Release 2021; 335:619-636. [PMID: 34116135 DOI: 10.1016/j.jconrel.2021.06.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 06/04/2021] [Accepted: 06/06/2021] [Indexed: 10/21/2022]
Abstract
The development of cell microencapsulation systems began several decades ago. However, today few systems have been tested in clinical trials. For this reason, in the last years, researchers have directed efforts towards trying to solve some of the key aspects that still limit efficacy and biosafety, the two major criteria that must be satisfied to reach the clinical practice. Regarding the efficacy, which is closely related to biocompatibility, substantial improvements have been made, such as the purification or chemical modification of the alginates that normally form the microspheres. Each of the components that make up the microcapsules has been carefully selected to avoid toxicities that can damage the encapsulated cells or generate an immune response leading to pericapsular fibrosis. As for the biosafety, researchers have developed biological circuits capable of actively responding to the needs of the patients to precisely and accurately release the demanded drug dose. Furthermore, the structure of the devices has been subject of study to adequately protect the encapsulated cells and prevent their spread in the body. The objective of this review is to describe the latest advances made by scientist to improve the efficacy and biosafety of cell microencapsulation systems for sustained drug delivery, also highlighting those points that still need to be optimized.
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Affiliation(s)
- Tania B Lopez-Mendez
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Edorta Santos-Vizcaino
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Jose Luis Pedraz
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), BTI Biotechnology Institute, Vitoria-Gasteiz, Spain; Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore.
| | - Rosa Maria Hernandez
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.
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17
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Li Q, Hou H, Li M, Yu X, Zuo H, Gao J, Zhang M, Li Z, Guo Z. CD73 + Mesenchymal Stem Cells Ameliorate Myocardial Infarction by Promoting Angiogenesis. Front Cell Dev Biol 2021; 9:637239. [PMID: 34055772 PMCID: PMC8152667 DOI: 10.3389/fcell.2021.637239] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 04/12/2021] [Indexed: 01/16/2023] Open
Abstract
With multipotent differentiation potential and paracrine capacity, mesenchymal stem cells (MSCs) have been widely applied in clinical practice for the treatment of ischemic heart disease. MSCs are a heterogeneous population and the specific population of MSCs may exhibit a selective ability for tissue repair. The aim of our research was to adapt the CD73+ subgroup of adipose derived MSCs (AD-MSCs) for the therapy of myocardial infarction (MI). In this research, AD-MSCs were isolated from adipose tissue surrounding the groin of mice and CD73+ AD-MSCs were sorted using flow cytometry. To investigate the therapeutic effects of CD73+ AD-MSCs, 1.2 × 106 CD73+ AD-MSCs were transplanted into rat model of MI, and CD73– AD-MSCs, normal AD-MSCs transplantation served as control. Our results revealed that CD73+ AD-MSCs played a more effective role in the acceleration function of cardiac recovery by promoting angiogenesis in a rat model of MI compared with mixed AD-MSCs and CD73– AD-MSCs. Moreover, with the expression of CD73 in AD-MSCs, the secretion of VEGF, SDF-1α, and HGF factors could be promoted. It also shows differences between CD73+ and CD73– AD-MSCs when the transcription profiles of these two subgroups were compared, especially in VEGF pathway. These findings raise an attractive outlook on CD73+ AD-MSCs as a dominant subgroup for treating MI-induced myocardial injury. CD73, a surface marker, can be used as a MSCs cell quality control for the recovery of MI by accelerating angiogenesis.
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Affiliation(s)
- Qiong Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Huifang Hou
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Meng Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Xia Yu
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Hongbo Zuo
- Xinxiang Central Hospital, Xinxiang, China
| | - Jianhui Gao
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Min Zhang
- Department of Hepatobiliary Surgery, Affiliated of Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Zongjin Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China.,Nankai University School of Medicine, Tianjin, China
| | - Zhikun Guo
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
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18
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Chae DS, Han S, Lee MK, Kim SW. Genome Edited Sirt1-Overexpressing Human Mesenchymal Stem Cells Exhibit Therapeutic Effects in Treating Collagen-Induced Arthritis. Mol Cells 2021; 44:245-253. [PMID: 33935044 PMCID: PMC8112166 DOI: 10.14348/molcells.2021.0037] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/18/2021] [Accepted: 04/01/2021] [Indexed: 12/15/2022] Open
Abstract
Even though mesenchymal stem cells (MSCs) are known for cartilage regeneration, their therapeutic efficacy needs to be enhanced. In the present study, we produced genome-edited silent information regulator 2 type 1 (Sirt1)-overexpressing MSCs, and evaluated their therapeutic potential in a damaged cartilage mouse liver fibrosis model. The Sirt1 gene was successfully inserted into a 'safe harbor' genomic locus in amniotic mesenchymal stem cells (AMMs), and the chondrogenic properties of the Sirt1 gene overexpressing AMMs (AMM/S) were characterized using quantitative PCR and histology. Therapeutic potentials were investigated in a collagen-induced arthritis (CIA) mouse model. Chondrocyte-differentiated AMM/S expressed cartilage-specific genes and were positive for Safranin O staining. Transplantation of AMM/S attenuated CIA progression and suppressed T helper (Th)-17 cell activation while increasing the Treg cell population in CIA mice. Pro-inflammatory factors, such as interleukin (IL)-1β, IL-6, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α were significantly decreased in AMM/S-injected joint tissues. In conclusion, genome-edited AMM/S may represent a safe and alternative therapeutic option for the treatment and repair of damaged cartilage, or in inflammatory joint arthritis.
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Affiliation(s)
- Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon 22711, Korea
| | - Seongho Han
- Department of Family Medicine, Dong-A University Medical Center, Dong-A University College of Medicine, Busan 49201, Korea
| | - Min-Kyung Lee
- Department of Dental Hygine, Dong-Eui Universtigy, Busan 47340, Korea
| | - Sung-Whan Kim
- Department Medicine, Catholic Kwandong University College of Medicine, Gangneung 25601, Korea
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19
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Um S, Ha J, Choi SJ, Oh W, Jin HJ. Prospects for the therapeutic development of umbilical cord blood-derived mesenchymal stem cells. World J Stem Cells 2020; 12:1511-1528. [PMID: 33505598 PMCID: PMC7789129 DOI: 10.4252/wjsc.v12.i12.1511] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/23/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord blood (UCB) is a primitive and abundant source of mesenchymal stem cells (MSCs). UCB-derived MSCs have a broad and efficient therapeutic capacity to treat various diseases and disorders. Despite the high latent self-renewal and differentiation capacity of these cells, the safety, efficacy, and yield of MSCs expanded for ex vivo clinical applications remains a concern. However, immunomodulatory effects have emerged in various disease models, exhibiting specific mechanisms of action, such as cell migration and homing, angiogenesis, anti-apoptosis, proliferation, anti-cancer, anti-fibrosis, anti-inflammation and tissue regeneration. Herein, we review the current literature pertaining to the UCB-derived MSC application as potential treatment strategies, and discuss the concerns regarding the safety and mass production issues in future applications.
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Affiliation(s)
- Soyoun Um
- Research Team for Immune Cell Therapy, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Jueun Ha
- Research Team for Osteoarthritis, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
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20
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Human Mesenchymal Stem Cells: The Present Alternative for High-Incidence Diseases, Even SARS-Cov-2. Stem Cells Int 2020; 2020:8892189. [PMID: 33414832 PMCID: PMC7769649 DOI: 10.1155/2020/8892189] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/06/2020] [Accepted: 11/24/2020] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs), defined as plastic adherent cells with multipotent differentiation capacity in vitro, are an emerging and valuable tool to treat a plethora of diseases due to their therapeutic mechanisms such as their paracrine activity, mitochondrial and organelle transfer, and transfer of therapeutic molecules via exosomes. Nowadays, there are more than a thousand registered clinical trials related to MSC application around the world, highlighting MSC role on difficult-to-treat high-incidence diseases such as the current COVID-19, HIV infections, and autoimmune and metabolic diseases. Here, we summarize a general overview of MSCs and their therapeutic mechanisms; also, we discuss some of the novel clinical trial protocols and their results as well as a comparison between the number of registries, countries, and search portals.
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21
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Udalamaththa VL, Kaluarachchi A, Wijeratne S, Udagama PV. Therapeutic uses of post-partum tissue-derived mesenchymal stromal cell secretome. Indian J Med Res 2020; 152:541-552. [PMID: 34145093 PMCID: PMC8224162 DOI: 10.4103/ijmr.ijmr_1450_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Indexed: 12/24/2022] Open
Abstract
Human post-partum tissue mesenchymal stromal cells (hPPT-MSCs) are widely used in research to investigate their differentiation capabilities and therapeutic effects as potential agents in cell-based therapy. This is ascribed to the advantages offered by the use of MSCs isolated from hPPT over other MSC sources. A paradigm shift in related research is evident that focuses on the secretome of the human MSCs (hMSCs), as therapeutic effects of hMSCs are attributed more so to their secreted growth factors, cytokines and chemokines and to the extracellular vesicles (EVs), all of which are components of the hMSC secretome. Positive therapeutic effects of the hPPT-MSC secretome have been demonstrated in diseases related to skin, kidney, heart, nervous system, cartilage and bones, that have aided fast recovery by replacing damaged, non-functional tissues, via differentiating and regenerating cells. Although certain limitations such as short half -life of the secretome components and irregular secreting patterns exist in secretome therapy, these issues are successfully addressed with the use of cutting-edge technologies such as genome editing and recombinant cytokine treatment. If the current limitations can be successfully overcome, the hPPT-MSC secretome including its EVs may be developed into a cost-effective therapeutic agent amenable to be used against a wide range of diseases/disorders.
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Affiliation(s)
| | - Athula Kaluarachchi
- Department of Obstetrics & Gynaecology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | | | - Preethi Vidya Udagama
- Department of Zoology & Environment Sciences, Faculty of Science, University of Colombo, Colombo, Sri Lanka
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22
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Yang C, Chen Y, Zhong L, You M, Yan Z, Luo M, Zhang B, Yang B, Chen Q. Homogeneity and heterogeneity of biological characteristics in mesenchymal stem cells from human umbilical cords and exfoliated deciduous teeth. Biochem Cell Biol 2020; 98:415-425. [PMID: 31794246 DOI: 10.1139/bcb-2019-0253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have proven powerful potential for cell-based therapy both in regenerative medicine and disease treatment. Human umbilical cords and exfoliated deciduous teeth are the main sources of MSCs with no donor injury or ethical issues. The goal of this study was to investigate the differences in the biological characteristics of human umbilical cord mesenchymal stem cells (UCMSCs) and stem cells from human exfoliated deciduous teeth (SHEDs). UCMSCs and SHEDs were identified by flow cytometry. The proliferation, differentiation, migration, chemotaxis, paracrine, immunomodulatory, neurite growth-promoting capabilities, and acetaldehyde dehydrogenase (ALDH) activity were comparatively studied between these two MSCs in vitro. The results showed that both SHEDs and UCMSCs expressed cell surface markers characteristic of MSCs. Furthermore, SHEDs exhibited better capacity for proliferation, migration, promotion of neurite growth, and chondrogenic differentiation. Meanwhile, UCMSCs showed more outstanding adipogenic differentiation and chemotaxy. Additionally, there were no significant differences in osteogenic differentiation, immunomodulatory capacity, and the proportion of ALDHBright compartment. Our findings indicate that although both UCMSCs and SHEDs are mesenchymal stem cells and presented some similar biological characteristics, they also have differences in many aspects, which might be helpful for developing future clinical cellular therapies.
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Affiliation(s)
- Chao Yang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Yu Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Liwu Zhong
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Min You
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Zhiling Yan
- Department of Stomatology, Chengdu Women's and Children's Central Hospital, Chengdu, China
| | - Maowen Luo
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Bo Zhang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Benyanzi Yang
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
| | - Qiang Chen
- Stem Cells and Regenerative Medicine Research Center, Sichuan Stem Cell Bank/Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, China
- Center for Stem Cell Research & Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, China
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Wang L, Zhao Y, Yang F, Feng M, Zhao Y, Chen X, Mi J, Yao Y, Guan D, Xiao Z, Chen B, Dai J. Biomimetic collagen biomaterial induces in situ lung regeneration by forming functional alveolar. Biomaterials 2020; 236:119825. [PMID: 32044576 DOI: 10.1016/j.biomaterials.2020.119825] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/07/2020] [Accepted: 01/25/2020] [Indexed: 01/02/2023]
Abstract
In situ restoration of severely damaged lung remains difficult due to its limited regeneration capacity after injury. Artificial lung scaffolds are emerging as potential substitutes, but it is still a challenge to reconstruct lung regeneration microenvironment in scaffold after lung resection injury. Here, a 3D biomimetic porous collagen scaffold with similar structure characteristics as lung is fabricated, and a novel collagen binding hepatocyte growth factor (CBD-HGF) is tethered on the collagen scaffold for maintaining the biomimetic function of HGF to improve the lung regeneration microenvironment. The biomimetic scaffold was implanted into the operative region of a rat partial lung resection model. The results revealed that vascular endothelial cells and endogenous alveolar stem cells entered the scaffold at the early stage of regeneration. At the later stage, inflammation and fibrosis were attenuated, the microvascular and functional alveolar-like structures were formed, and the general morphology of the injured lung was restored. Taken together, the functional 3D biomimetic collagen scaffold facilitates recovery of the injured lung, alveolar regeneration, and angiogenesis after acute lung injury. Particularly, this is the first study of lung regeneration in vivo guided by biomimetic collagen scaffold materials, which supports the concept that tissue engineering is an effective strategy for alveolar regeneration.
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Affiliation(s)
- Linjie Wang
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yannan Zhao
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Feng Yang
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Meng Feng
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yazhen Zhao
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xi Chen
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Junwei Mi
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yuanjiang Yao
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Dongwei Guan
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Zhifeng Xiao
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Bing Chen
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Jianwu Dai
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
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25
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Wang L, Liu T, Liang R, Wang G, Liu Y, Zou J, Liu N, Zhang B, Liu Y, Ding X, Cai X, Wang Z, Xu X, Ricordi C, Wang S, Shen Z. Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation. EBioMedicine 2020; 51:102615. [PMID: 31918404 PMCID: PMC7000334 DOI: 10.1016/j.ebiom.2019.102615] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 12/05/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Background A physiological hallmark of patients with type 2 diabetes mellitus (T2DM) is β cell dysfunction. Despite adequate treatment, it is an irreversible process that follows disease progression. Therefore, the development of novel therapies that restore β cell function is of utmost importance. Methods This study aims to unveil the mechanistic action of mesenchymal stem cells (MSCs) by investigating its impact on isolated human T2DM islets ex vivo and in vivo. Findings We propose that MSCs can attenuate β cell dysfunction by reversing β cell dedifferentiation in an IL-1Ra-mediated manner. In response to the elevated expression of proinflammatory cytokines in human T2DM islet cells, we observed that MSCs was activated to secret IL-1R antagonist (IL-1Ra) which acted on the inflammed islets and reversed β cell dedifferentiation, suggesting a crosstalk between MSCs and human T2DM islets. The co-transplantation of MSCs with human T2DM islets in diabetic SCID mice and intravenous infusion of MSCs in db/db mice revealed the reversal of β cell dedifferentiation and improved glycaemic control in the latter. Interpretation This evidence highlights the potential of MSCs in future cell-based therapies regarding the amelioration of β cell dysfunction.
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Affiliation(s)
- Le Wang
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
| | - Tengli Liu
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
| | - Rui Liang
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
| | - Guanqiao Wang
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Yaojuan Liu
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
| | - Jiaqi Zou
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
| | - Na Liu
- NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China
| | - Boya Zhang
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Yan Liu
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Xuejie Ding
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Xiangheng Cai
- The First Central Clinical College, Tianjin Medical University, Tianjin, 300192, China
| | - Zhiping Wang
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Xiumin Xu
- Diabetes Research Institute, Cell Transplant Centre; Department of Surgery; Department Medicine; Miller School of Medicine, University of Miami, Miami, FL 33136, USA; The Cure Alliance, Miami, FL 33137, USA; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
| | - Camillo Ricordi
- Diabetes Research Institute, Cell Transplant Centre; Department of Surgery; Department Medicine; Miller School of Medicine, University of Miami, Miami, FL 33136, USA; The Cure Alliance, Miami, FL 33137, USA; Diabetes Research Institute Federation, Hollywood, FL 33021, USA
| | - Shusen Wang
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; NHC Key Laboratory for Critical Care Medicine, Tianjin 300384, China; Diabetes Research Institute Federation, Hollywood, FL 33021, USA.
| | - Zhongyang Shen
- Organ Transplant Centre, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China.
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26
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Impact of renal ischemia/reperfusion injury on the rat Kupffer cell as a remote cell: A biochemical, histological, immunohistochemical, and electron microscopic study. Acta Histochem 2019; 121:575-583. [PMID: 31078256 DOI: 10.1016/j.acthis.2019.04.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/12/2019] [Accepted: 04/15/2019] [Indexed: 02/08/2023]
Abstract
Almost all transplanted solid organs are exposed to some degree of ischemia-reperfusion (IR) damage. It is interesting to know that this IR damage affects various remote tissues including the liver and resulted in serious adverse effects. Liver injury triggers different responses of liver tissue especially Kupffer cells (KCs). The goal of this current study is to assess the biochemical and morphological changes of hepatic KCs after the induction of renal ischemia-reperfusion (RIR) and point out their role in remote liver injury after RIR. Sixteen male Sprague-Dawley rats were randomly divided into two equal groups: Group I; sham group. Group II; renal ischemia reperfusion (IR) group in which rats were exposed to renal ischemia for 45 min followed by renal reperfusion for 48 h. Three rats from each group were subjected to charcoal injection to evaluate KCs activity. Specimens of rat liver from each group were obtained and processed for biochemical, light microscopic and ultramicroscopic examination. The current results showed elevated serum levels of AST and ALT. The liver HGF-α protein expression increased in IR group compared to the sham group. In IR group, numerous charcoal labeled KCs were observed mainly localized around the central vein. Scanning electron micrographs showed complex primary and secondary foot process of the KCs. Ultrastructural study showed KCs with multiple cytoplasmic vacuoles, lysosomes and mitochondria, rough endoplasmic reticulum and ribosomes. Immuno-histochemical study showed more tumor necrosis factor-α (TNF-α) expression in KCs than the sham group. These results collectively demonstrated that renal IR produced biochemical and morphological changes in the liver KCs and theses cells might have a role in the remote liver injury after renal IR. This might be one of the mechanisms through which RIR affects the liver.
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27
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Advanced drug delivery systems and artificial skin grafts for skin wound healing. Adv Drug Deliv Rev 2019; 146:209-239. [PMID: 30605737 DOI: 10.1016/j.addr.2018.12.014] [Citation(s) in RCA: 367] [Impact Index Per Article: 61.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/27/2018] [Accepted: 12/27/2018] [Indexed: 12/14/2022]
Abstract
Cutaneous injuries, especially chronic wounds, burns, and skin wound infection, require painstakingly long-term treatment with an immense financial burden to healthcare systems worldwide. However, clinical management of chronic wounds remains unsatisfactory in many cases. Various strategies including growth factor and gene delivery as well as cell therapy have been used to enhance the healing of non-healing wounds. Drug delivery systems across the nano, micro, and macroscales can extend half-life, improve bioavailability, optimize pharmacokinetics, and decrease dosing frequency of drugs and genes. Replacement of the damaged skin tissue with substitutes comprising cell-laden scaffold can also restore the barrier and regulatory functions of skin at the wound site. This review covers comprehensively the advanced treatment strategies to improve the quality of wound healing.
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Deryabin P, Griukova A, Shatrova A, Petukhov A, Nikolsky N, Borodkina A. Optimization of lentiviral transduction parameters and its application for CRISPR-based secretome modification of human endometrial mesenchymal stem cells. Cell Cycle 2019; 18:742-758. [PMID: 30880567 PMCID: PMC6464586 DOI: 10.1080/15384101.2019.1593650] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/08/2019] [Accepted: 02/19/2019] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stem cells (MSCs) hold a great promise for successful development of regenerative medicine. Among the plenty of uncovered MSCs sources, desquamated endometrium collected from the menstrual blood probably remains the most accessible. Though numerous studies have been published on human endometrium-derived mesenchymal stem cells (hMESCs) properties in the past years, there are only a few data regarding their genetic modulation. Moreover, there is a lack of information about the fate of the transduced hMESCs. The present study aimed to optimize hMESCs transduction parameters and apply Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology for genome and secretome modification. The fate of hMESCs transduced either in presence of polybrene (Pb) or protamine sulfate (Ps) was assessed by alterations in CD expression profile, growth rate, cell size, migration capability, osteogenic, adipogenic, and decidual differential potentials. Here, we postulated that the use of Ps for hMESCs genetic manipulations is preferable, as it has no impact on the stem-cell properties, whereas Pb application is undesirable, as it induces cellular senescence. Plasminogen activator inhibitor-1 was selected for further targeted hMESCs genome and secretome modification using CRISPR/Cas9 systems. The obtained data provide optimized transduction scheme for hMESCs and verification of its effectiveness by successful hMESCs genome editing via CRISPR/Cas9 technology.
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Affiliation(s)
- Pavel Deryabin
- Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia
| | - Anastasiia Griukova
- Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia
| | - Alla Shatrova
- Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia
| | - Alexey Petukhov
- Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia
- Almazov National Medical Research Centre, Saint-Petersburg, Russia
| | - Nikolay Nikolsky
- Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, Russia
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29
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Cho HM, Cho JY. Prediction of therapeutic effects of human cardiomyocytes in myocardial infarction using non-human primates model. ANNALS OF TRANSLATIONAL MEDICINE 2019; 6:S64. [PMID: 30613639 DOI: 10.21037/atm.2018.10.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Hyun-Min Cho
- Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
| | - Je-Yoel Cho
- Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea
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30
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Abstract
Mesenchymal stromal cell (MSC) therapy has produced very promising results for multiple diseases in animal models, with over 780 clinical trials on going or completed. However, most of the human clinical trials have not been as successful as trials using preclinical models. To improve the therapeutic potential of MSCs, different research groups have used gene transfer vectors to express factors involved in migration, survival, differentiation, and immunomodulation. The ideal gene transfer vector for most applications should achieve long-term, stable (constitutive or inducible) transgene expression in MSCs and their progeny. Given their efficiency and low impact on transduced cells, lentiviral vectors (LVs) are the vectors of choice. In this chapter we will describe a detailed protocol for the generation of genetically modified MSCs using lentiviral vectors (LVs). Although this protocol has been optimized for MSC lentiviral transduction, it can be easily adapted to other stem cells by changing culture conditions while maintaining volumes and incubation times.
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31
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Choi JS, Jeong IS, Han JH, Cheon SH, Kim SW. IL-10-secreting human MSCs generated by TALEN gene editing ameliorate liver fibrosis through enhanced anti-fibrotic activity. Biomater Sci 2019; 7:1078-1087. [DOI: 10.1039/c8bm01347k] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Interleukin 10 secreting genome-edited MSCs inhibited liver fibrosis and ameliorated abnormal liver function.
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Affiliation(s)
- Ja Sung Choi
- Department of Internal Medicine
- Catholic Kwandong University College of Medicine
- International St. Mary's Hospital
- Incheon
- Republic of Korea
| | - In Sil Jeong
- Department Medicine
- Catholic Kwandong University College of Medicine
- Gangneung
- Republic of Korea
| | - Ju Hye Han
- Department Medicine
- Catholic Kwandong University College of Medicine
- Gangneung
- Republic of Korea
| | - Sae Hee Cheon
- Department of Dental Hygiene
- Masan University
- Masan
- Korea
| | - Sung-Whan Kim
- Department Medicine
- Catholic Kwandong University College of Medicine
- Gangneung
- Republic of Korea
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Coronary stents with inducible VEGF/HGF-secreting UCB-MSCs reduced restenosis and increased re-endothelialization in a swine model. Exp Mol Med 2018; 50:1-14. [PMID: 30174328 PMCID: PMC6119684 DOI: 10.1038/s12276-018-0143-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 05/30/2018] [Accepted: 06/07/2018] [Indexed: 12/12/2022] Open
Abstract
Atherosclerotic plaques within the vasculature may eventually lead to heart failure. Currently, cardiac stenting is the most effective and least invasive approach to treat this disease. However, in-stent restenosis is a complex chronic side effect of stenting treatment. This study used coronary stents coated with stem cells secreting angiogenic growth factors via an inducible genome-editing system to reduce stent restenosis and induce re-endothelialization within the artery. The characteristics of the cells and their adhesion properties on the stents were confirmed, and the stents were transplanted into a swine model to evaluate restenosis and the potential therapeutic use of stents with stem cells. Restenosis was evaluated using optical coherence tomography (OCT), microcomputed tomography (mCT) and angiography, and re-endothelialization was evaluated by immunostaining after cardiac stent treatment. Compared to a bare metal stent (BMS) or a parental umbilical cord blood-derived mesenchymal stem cell (UCB-MSC)-coated stent, the stents with stem cells capable of the controlled release of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) successfully reduced restenosis within the stent and induced natural re-endothelialization. Furthermore, UCB-MSCs exhibited the ability to differentiate into endothelial cells in Matrigel, and HGF and VEGF improved this differentiation. Our study indicates that stents coated with UCB-MSCs secreting VEGF/HGF reduce the restenosis side effects of cardiac stenting with improved re-endothelialization.
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Jiang J, Wang Y, Liu B, Chen X, Zhang S. Challenges and research progress of the use of mesenchymal stem cells in the treatment of ischemic stroke. Brain Dev 2018; 40:612-626. [PMID: 29661589 DOI: 10.1016/j.braindev.2018.03.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 03/28/2018] [Accepted: 03/29/2018] [Indexed: 02/06/2023]
Abstract
Cerebral Ischemic Stroke (CIS) has become a hot issue in medical research because of the diversity of risk factors and the uncertainty of prognosis. In the field of regenerative medicine, mesenchymal stem cells (MSCs) have an increasingly prominent position due to their advantages of multiple differentiation, low immunogenicity and wide application. In the basic and clinical research of CIS, there are still some problems to be solved in the treatment of CIS. This paper will discuss the progresses and some obstacles of current MSCs for the treatment of CIS.
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Affiliation(s)
- Jipeng Jiang
- Institution of Brain Trauma and Neurology Disease of Affiliated Hospital of Logistics University of People's Armed Police Forces, Chenglin Road No. 220, Tianjin 300162, China.
| | - Yuting Wang
- Tianjin Medical University, Qixiangtai Road No. 22, Tianjin 300070, China
| | - Baohu Liu
- Tianjin University of Traditional Chinese Medicine, Yuquan Road No. 88, Tianjin 300193, China
| | - Xuyi Chen
- Institution of Brain Trauma and Neurology Disease of Affiliated Hospital of Logistics University of People's Armed Police Forces, Chenglin Road No. 220, Tianjin 300162, China
| | - Sai Zhang
- Institution of Brain Trauma and Neurology Disease of Affiliated Hospital of Logistics University of People's Armed Police Forces, Chenglin Road No. 220, Tianjin 300162, China.
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Lee BNR, Chang HK, Son YS, Lee D, Kwon SM, Kim PH, Cho JY. IFN-γ enhances the wound healing effect of late EPCs (LEPCs) via BST2-mediated adhesion to endothelial cells. FEBS Lett 2018; 592:1705-1715. [PMID: 29710419 DOI: 10.1002/1873-3468.13078] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/01/2018] [Accepted: 04/18/2018] [Indexed: 12/22/2022]
Abstract
Circulating late endothelial progenitor cells (LEPCs) home to injured vessels, initiating blood vessel regeneration. This process requires the initial adhesion of LEPCs to endothelial cells within the wounded site. In this study, treating LEPCs with IFN-γ enhanced wound healing through BST2-mediated adhesion to endothelial cells. We found that IFN-γ significantly upregulated BST2 expression in both LEPCs and ECs and increased tube formation in LEPCs. Upregulated BST2 increased LEPC adhesion to ECs through a tight homophilic interaction of its extracellular domain. Finally, when the IFN-γ-treated LEPCs were injected into the wounded mouse tail vein, superior therapeutic effects of wound closure were observed. This study provides a useful application to enhance the adhesion of LEPCs for vessel regeneration and wound closure.
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Affiliation(s)
- Bom Nae Rin Lee
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, Korea
| | - Hyun-Kyung Chang
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, Korea
| | - Yeon Sung Son
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, Korea
| | - Dabin Lee
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, Korea
| | - Sang-Mo Kwon
- Laboratory for Vascular Medicine & Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan, Korea
| | - Pyung-Hwan Kim
- Department of Biomedical Laboratory Science, College of Medical Science, Konyang University, Daejeon, Korea
| | - Je-Yoel Cho
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, Korea
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35
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Kang I, Lee BC, Choi SW, Lee JY, Kim JJ, Kim BE, Kim DH, Lee SE, Shin N, Seo Y, Kim HS, Kim DI, Kang KS. Donor-dependent variation of human umbilical cord blood mesenchymal stem cells in response to hypoxic preconditioning and amelioration of limb ischemia. Exp Mol Med 2018; 50:1-15. [PMID: 29674661 PMCID: PMC5938050 DOI: 10.1038/s12276-017-0014-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 11/05/2017] [Accepted: 11/09/2017] [Indexed: 01/19/2023] Open
Abstract
With the rapidly growing demand for mesenchymal stem cell (MSC) therapy, numerous strategies using MSCs for different diseases have been studied and reported. Because of their immunosuppressive properties, MSCs are commonly used as an allogeneic treatment. However, for the many donors who could potentially be used, it is important to understand the capacity for therapeutic usage with donor-to-donor heterogeneity. In this study, we aimed to investigate MSCs as a promising therapeutic strategy for critical limb ischemia. We evaluated MSCs from two donors (#55 and #64) and analyzed the capacity for angiogenesis through in vivo and in vitro assays to compare the therapeutic effect between different donors. We emphasized the importance of intra-population heterogeneity of MSCs on therapeutic usage by evaluating the effects of hypoxia on activating cellular angiogenesis in MSCs. The precondition of hypoxia in MSCs is known to enhance therapeutic efficacy. Our study suggests that sensitivity to hypoxic conditions is different between cells originating from different donors, and this difference affects the contribution to angiogenesis. The bioinformatics analysis of different donors under hypoxic culture conditions identified intrinsic variability in gene expression patterns and suggests alternative potential genetic factors ANGPTL4, ADM, SLC2A3, and CDON as guaranteed general indicators for further stem cell therapy.
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Affiliation(s)
- Insung Kang
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Chul Lee
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Soon Won Choi
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jin Young Lee
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Jae-Jun Kim
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Bo-Eun Kim
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Da-Hyun Kim
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Seung Eun Lee
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Nari Shin
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yoojin Seo
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Pusan National University School of Medicine, Busan, 49241, Republic of Korea.,Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, Republic of Korea
| | - Hyung-Sik Kim
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.,Pusan National University School of Medicine, Busan, 49241, Republic of Korea.,Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, Republic of Korea
| | - Dong-Ik Kim
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Kyung-Sun Kang
- Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. .,Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.
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Wang LS, Wang H, Zhang QL, Yang ZJ, Kong FX, Wu CT. Hepatocyte Growth Factor Gene Therapy for Ischemic Diseases. Hum Gene Ther 2018; 29:413-423. [DOI: 10.1089/hum.2017.217] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Li-Sheng Wang
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
- School of Nursing, Jilin University, Jilin, P.R. China
| | - Hua Wang
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Qing-Lin Zhang
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Zhi-Jian Yang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
| | - Fan-Xuan Kong
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
| | - Chu-Tse Wu
- Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, P.R. China
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37
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Jeong IS, Park Y, Ryu HA, An HS, Han JH, Kim SW. Dual chemotactic factors-secreting human amniotic mesenchymal stem cells via TALEN-mediated gene editing enhanced angiogenesis. Int J Cardiol 2018; 260:156-162. [PMID: 29506937 DOI: 10.1016/j.ijcard.2018.02.043] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 02/09/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND Even though mesenchymal stem cells (MSCs) have angiogenic property, their cytokine secretory capacity is limited to treat ischemic vascular disorders. In present study, we produced genome-edited MSCs that secreted dual chemokine granulocyte chemotactic protein-2 (GCP-2) and stromal-derived factor-1α (SDF-1α) and determined their therapeutic potential in the context of experimental ischemia. METHODS GCP-2 and SDF-1α genes were integrated into safe harbor site at the safe harbor genomic locus of amniotic mesenchymal stem cells (AMM) via transcription activator-like effector nucleases (TALEN). GCP-2 and SDF-1α gene-edited AMM (AMM/GS) were used for quantitative (q)-PCR, Matrigel tube formation, cell migration, Matrigel plug assays and in vivo therapeutic assays using hindlimb ischemia mouse model. RESULTS AMM/GS-derived culture media (CM) induced significantly higher tube lengths and branching points as compared to AMM/S CM and AMM CM. Interestingly, Matrigel plug assays revealed that significantly higher levels of red blood cells were found in AMM/GS than AMM/S and AMM Matigel plugs and exhibited micro-vascular like formation. Cells was transplanted into ischemic mouse hindlimbs and compared with control groups. AMM/GS injection prevented limb loss and augmented blood perfusion, suggesting that enhances neovascularization in hindlimb ischemia. In addition, transplanted AMM/GS revealed high vasculogenic potential in vivo compared with transplanted AMM/S. CONCLUSION Taken together, genome-edited MSCs that express dual chemokine GCP-2 and SDF-1α might be alternative therapeutic options for the treatment of ischemic vascular disease.
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Affiliation(s)
- In Sil Jeong
- Institute for Bio-Medical Convergence, Department of Medicine, Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea; Catholic Kwandong University International St. Mary's Hospital, Incheon, Metropolitan City, Republic of Korea
| | - Youngjin Park
- Department of Family Medicine, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Hyun Aae Ryu
- Institute for Bio-Medical Convergence, Department of Medicine, Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea; Catholic Kwandong University International St. Mary's Hospital, Incheon, Metropolitan City, Republic of Korea
| | - Hyun Sook An
- Il Sin Christian Hospital, Busan, Republic of Korea
| | - Ju Hye Han
- Institute for Bio-Medical Convergence, Department of Medicine, Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea; Catholic Kwandong University International St. Mary's Hospital, Incheon, Metropolitan City, Republic of Korea
| | - Sung-Whan Kim
- Institute for Bio-Medical Convergence, Department of Medicine, Catholic Kwandong University College of Medicine, Gangneung, Republic of Korea; Catholic Kwandong University International St. Mary's Hospital, Incheon, Metropolitan City, Republic of Korea.
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38
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Gonzalez-Pujana A, Orive G, Pedraz JL, Santos-Vizcaino E, Hernandez RM. Alginate Microcapsules for Drug Delivery. SPRINGER SERIES IN BIOMATERIALS SCIENCE AND ENGINEERING 2018. [DOI: 10.1007/978-981-10-6910-9_3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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39
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Gonzalez-Pujana A, Santos E, Orive G, Pedraz JL, Hernandez RM. Cell microencapsulation technology: Current vision of its therapeutic potential through the administration routes. J Drug Deliv Sci Technol 2017. [DOI: 10.1016/j.jddst.2017.03.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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40
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Zhou Y, Tsai TL, Li WJ. Strategies to retain properties of bone marrow-derived mesenchymal stem cells ex vivo. Ann N Y Acad Sci 2017; 1409:3-17. [PMID: 28984359 DOI: 10.1111/nyas.13451] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/05/2017] [Accepted: 07/18/2017] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) have been extensively used for cell therapies and tissue engineering. The current MSC strategy requires a large quantity of cells for such applications, which can be achieved through cell expansion in culture. In the body, stem cell fate is largely determined by their microenvironment, known as the niche. The complex and dynamic stem cell niche provides physical, mechanical, and chemical cues to collaboratively regulate cell activities. It remains a great challenge to maintain the properties of MSCs in culture. Constructing a microenvironment as an engineered stem cell niche in culture to maintain MSC phenotypes, properties, and functions is a viable strategy to address the issue. Here, we review the current understanding of MSC behavior in the bone marrow niche, describe different strategies to engineer an in vitro microenvironment for maintaining MSC properties and functions, and discuss previous findings on environmental factors critical to the modulation of MSC activities in engineered microenvironments.
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Affiliation(s)
- Yaxian Zhou
- Laboratory of Musculoskeletal Biology and Regenerative Medicine, Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, Wisconsin.,Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin
| | - Tsung-Lin Tsai
- Laboratory of Musculoskeletal Biology and Regenerative Medicine, Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, Wisconsin.,Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin
| | - Wan-Ju Li
- Laboratory of Musculoskeletal Biology and Regenerative Medicine, Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, Wisconsin.,Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin
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Lee BNR, Son YS, Lee D, Choi YJ, Kwon SM, Chang HK, Kim PH, Cho JY. Hedgehog-Interacting Protein (HIP) Regulates Apoptosis Evasion and Angiogenic Function of Late Endothelial Progenitor Cells. Sci Rep 2017; 7:12449. [PMID: 28963460 PMCID: PMC5622095 DOI: 10.1038/s41598-017-12571-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 07/14/2017] [Indexed: 11/16/2022] Open
Abstract
Late endothelial progenitor cells (LEPCs) are derived from mononuclear cells (MNCs) and are thought to directly incorporate into blood vessels and differentiate into mature endothelial cells (ECs). Using transcriptome and proteome analysis, we identified distinctive LEPC profiles and found that Hedgehog-interacting protein (HIP) is strongly expressed in LEPCs. Inhibition of HIP by lentiviral knockdown activated canonical hedgehog signaling in LEPCs, while it activated non-canonical hedgehog signaling in ECs. In LEPCs, HIP knockdown induced much enhanced tube formation and resistance to apoptosis under oxidative stress conditions via canonical hedgehog signaling. Although HIP is strongly expressed in proliferating LEPCs, HIP expression is down-regulated during angiogenesis and under oxidative stress condition. Moreover, when LEPCs are treated with angiogenic triggers such as VEGF and FGF2, HIP expression is reduced. Our findings suggest that HIP blocks LEPC angiogenesis and regulate survival when there is no angiogenic stimulation. HIP inhibition in LEPCs enhanced tube formation and reduced apoptosis, resulting in improved angiogenesis.
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Affiliation(s)
- Bom Nae Rin Lee
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea
| | - Yeon Sung Son
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea
| | - Dabin Lee
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea
| | - Young-Jin Choi
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea
| | - Sang-Mo Kwon
- Laboratory for Vascular Medicine & Stem Cell Biology, Medical Research Institute, Department of Physiology, School of Medicine, Pusan National University, Yangsan, 626-870, Korea
| | - Hyun-Kyung Chang
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea
| | - Pyung-Hwan Kim
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea
- Department of Biomedical Laboratory Science, College of Medical Science, Konyang University, Daejeon, 35-365, Korea
| | - Je-Yoel Cho
- Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul, 151-742, Korea.
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Han KH, Kim AK, Kim DI. Therapeutic Potential of Human Mesenchymal Stem Cells for Treating Ischemic Limb Diseases. Int J Stem Cells 2016; 9:163-168. [PMID: 27871151 PMCID: PMC5155711 DOI: 10.15283/ijsc16053] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2016] [Indexed: 12/19/2022] Open
Abstract
Ischemic limb diseases are induced by different obstructions of peripheral arteries. These obstructions result in insufficient nutrient and oxygen supplies to the extremities, thereby leading to severe tissue damage that is in turn related to severe morbidities and mortalities. Mesenchymal stem cells (MSCs) have been isolated from various sources. These cells are multipotent with respect to differentiation and are also characterized by migration, immune suppression, and secretion of paracrine factors. Mesenchymal stem cells have been proposed to have therapeutic potential for the treatment of ischemic limb diseases. In preclinical experiments, injection of single MSCs has been shown to increase angiogenesis and blood flow in ischemic hindlimb animal models; several molecular mechanisms of angiogenesis have also been elucidated. Furthermore, modified strategies have been developed for enhancing angiogenesis and the efficacy of MSCs. These strategies have demonstrated significant effects in pre-clinical studies. In clinical trials, MSCs have shown significant effects in the treatment of ischemic limb diseases. In this review, we focus on the therapeutic properties of human MSCs and the modified methods for enhancing angiogenesis in pre-clinical experiments. We also discuss the clinical applications of MSCs for treating limb ischemia.
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Affiliation(s)
- Kyu-Hyun Han
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ae-Kyeong Kim
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong-Ik Kim
- Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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