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Sato S, Teramura Y, Ogawa Y, Shimizu E, Otake M, Hori K, Kamata T, Shu Y, Seta Y, Kuramochi A, Asai K, Shimizu S, Negishi K, Hirayama M. Conditioned media of stem cells from human exfoliated deciduous teeth contain factors related to extracellular matrix organization and promotes corneal epithelial wound healing. Regen Ther 2025; 29:148-161. [PMID: 40170802 PMCID: PMC11960544 DOI: 10.1016/j.reth.2025.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/27/2025] [Accepted: 03/09/2025] [Indexed: 04/03/2025] Open
Abstract
This study aimed to investigate the therapeutic potential of cell-free conditioned media (CM) from human mesenchymal stem cells (hMSCs), specifically stem cells from human exfoliated deciduous teeth (SHED), for treating ocular surface diseases. The proteomes of various hMSC-CMs were compared using cytokine array and liquid chromatography-mass spectrometry (LC-MS). Bioinformatic analysis identified key biological pathways associated with SHED-CM, immortalized SHED-CM (IM-SHED-CM), and a fractionated component of IM-SHED-CM in which low weight molecules (less than 3.5kD) were depleted. Corneal epithelial wound healing models were constructed by epithelial scraping and treated with eye drops derived from SHED-CM. For the migration assay, the human corneal epithelial cells were wounded and then incubated with SHED-CM. SHED-CM, IM-SHED-CM, and >3.5 kD fractionated component eyedrops were administered to a chronic graft-versus-host disease (cGVHD) mouse model with sever corneal epithelial damages. SHED-CM, IM-SHED-CM, and >3.5 kD fractionated component of IM-SHED-CM were enriched in factors involved in epithelial wound healing, particularly extracellular matrix (ECM) organization. Both in vitro and in vivo assays demonstrated that SHED-CM significantly enhanced corneal epithelial wound healing. Furthermore, SHED-CM-derived eye drops reduced corneal epithelial damage, inflammatory cell infiltration, and oxidative stress in the corneal epithelium and maintained the expression of limbal stem cell markers in the cGVHD mouse model. These findings suggest that SHED-CM eye drops could be a novel treatment for corneal epithelial damage, highlighting the role of bioactive factors in promoting wound healing and offering an alternative to cell-based MSC therapies for corneal wound healing.
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Affiliation(s)
- Shinri Sato
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yuji Teramura
- Cellular and Molecular Biotechnology Research Institute (CMB), National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
- Department of Immunology, Genetics and Pathology (IGP), Uppsala University, Dag Hammarskjölds väg 20, SE-751 85, Uppsala, Sweden
- Master's/Doctoral Program in Life Science Innovation (T-LSI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Eisuke Shimizu
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masato Otake
- U-Factor Co., Ltd., 1F ESCALIER Rokubancho, 7-11 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Keigo Hori
- U-Factor Co., Ltd., 1F ESCALIER Rokubancho, 7-11 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Takamitsu Kamata
- U-Factor Co., Ltd., 1F ESCALIER Rokubancho, 7-11 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Yujing Shu
- U-Factor Co., Ltd., 1F ESCALIER Rokubancho, 7-11 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Yasuhiro Seta
- Hitonowa Medical, K. PLAZA 2F, 1-7 Rokubancho, Chiyoda-ku, Tokyo 102-0085, Japan
| | - Akiko Kuramochi
- Cellular and Molecular Biotechnology Research Institute (CMB), National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
| | - Kazuki Asai
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Shota Shimizu
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Kazuno Negishi
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masatoshi Hirayama
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Sao K, Risbud MV. SDC4 drives fibrotic remodeling of the intervertebral disc under altered spinal loading. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.13.643128. [PMID: 40161806 PMCID: PMC11952502 DOI: 10.1101/2025.03.13.643128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Alterations in physiological loading of the spine are deleterious to intervertebral disc health. The caudal spine region Ca3-6 that experiences increased flexion, showed disc degeneration in young adult mice. Given the role of Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan in disc matrix catabolism and mechanosensing, we investigated if deletion could mitigate this loading-dependent phenotype. Notably, at spinal levels Ca3-6, Sdc4- KO mice did not exhibit increased collagen fibril and fibronectin deposition in the NP compartment or showed the alterations in collagen crosslinks observed in wild-type mice. Similarly, unlike wild-type mice, NP cells in Sdc4 -KO mice retained transgelin (TGLN) expression and showed absence of COL X deposition, pointing to the preservation of their notochordal characteristics. Proteomic analysis revealed that NP tissues responded to the abnormal loading by increasing the abundance of proteins associated with extracellular matrix remodeling, chondrocyte development, and contractility. Similarly, downregulated proteins suggested decreased vesicle transport, autophagy-related pathway, and RNA quality control regulation. Notably, NP proteome from Sdc4 KO suggested that increased dynamin-mediated endocytosis, autophagy-related pathway, and RNA and DNA quality control may underscore the protection from increased flexion-induced degeneration. Our study highlights the important role of SDC4 in fine-tuning cellular homeostasis and extracellular matrix production in disc environment subjected to altered loading.
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Gerlza T, Trojacher C, Fuchs T, Atlic A, Weis R, Adage T, Kungl AJ. Designing a CXCL8-hsa chimera as potential immunmodulator of the tumor micro-environment. Front Immunol 2025; 16:1539733. [PMID: 40124384 PMCID: PMC11926544 DOI: 10.3389/fimmu.2025.1539733] [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: 12/04/2024] [Accepted: 02/13/2025] [Indexed: 03/25/2025] Open
Abstract
Introduction CXCL8, belonging to inflammatory chemokines, is expressed by various cell types and plays a key role in leukocyte trafficking during infections, inflammatory processes, tissue injury and tumor progression. Chemokines interact not only with G-protein coupled receptors but also with glycosaminoglycans (GAGs), which are polyanionic linear polysaccharides. Chemokine-GAG interactions are critical for creating localized concentration gradients, protecting chemokines from degradation, and maintaining their efficacy in vivo. Methods We have previously engineered a CXCL8-based dominant-negative decoy ("PA401") with strongly increased GAG binding affinity combined with complete GPCR knockout, which was originally developed for the treatment of COPD. Here we have optimized our engineering protocol by minimizing CXCL8 mutations while conserving its in vitro dominant-negative activities. This novel CXCL8-based decoy (mtCXCL8) was further fused to human serum albumin (HSA) to overcome the typically very short serum half-life of chemokine-based biologics. We are therefore able to present here an entirely novel CXCL8-based biologic (hsa/mtCXCL8) which reflects our threefold modification strategy - increasing GAG-binding affinity by minimal mutagenesis, GPCR knockout, and fusion to HSA - thus representing a comprehensive and novel approach towards addressing chronic CXCL8-driven diseases. Results In the current study, we have investigated the immunomodulatory potential of our new decoy in a 3-D cellular tumor model ("BioMAP") which relates the biomarker interaction profile of immune and tumor cells to a data-base mirrored biomarker read-out. The obtained BioMAP results suggest an impact of hsa/mtCXCL8 on the immune compartment of the VascHT29 cell model by modulating cytokine levels and inhibiting immune cell activation markers. When combined with Keytruda (Pembrolizumab), a PD-1 inhibitor, it enhances some of its known activities, indicating potential synergistic effects, but further investigation is needed due to the observed increase in soluble IL-6 and limitations in dose selection for future in vivo studies. Discussion By prolonging the presence of engineered chemokine mutants in the bloodstream and optimizing their stability, these strategies aim to enhance the therapeutic efficacy of CXCL8-based interventions, offering promising avenues for the treatment of several CXCL8-mediated pathologies, including cancer.
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Affiliation(s)
- Tanja Gerlza
- Karl-Franzens-University Graz, Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Graz, Austria
| | - Christina Trojacher
- Karl-Franzens-University Graz, Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Graz, Austria
| | - Thomas Fuchs
- Medical University Graz, Otto Loewi Research Center, Graz, Austria
| | | | | | | | - Andreas J. Kungl
- Karl-Franzens-University Graz, Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Graz, Austria
- Antagonis Biotherapeutics GmbH, Graz, Austria
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Liu S, Zhang R, Hallajzadeh J. Role of exercise on ncRNAs and exosomal ncRNAs in preventing neurodegenerative diseases: a narrative review. Mol Med 2025; 31:51. [PMID: 39920595 PMCID: PMC11803956 DOI: 10.1186/s10020-025-01091-y] [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: 07/27/2024] [Accepted: 01/17/2025] [Indexed: 02/09/2025] Open
Abstract
Engaging in activity has proven to have beneficial effects on different facets of well-being, such as conditions related to the deterioration of the nervous system. Non-coding RNAs (ncRNAs) and exosomal ncRNAs associated with vesicles have been recognized as influencers of gene expression and cell signaling, potentially contributing to the positive impact of physical activity on neurodegenerative conditions. It is hypothesized that exercise-induced changes in ncRNA expression may regulate key processes involved in neuroprotection, including neuroinflammation, oxidative stress, protein aggregation, and synaptic function. Exercise has shown promise in preventing neurodegenerative diseases (NDs), and ncRNAs and exosomal ncRNAs are emerging as potential mediators of these benefits. In review, we explored how ncRNAs and exosomal ncRNAs play a role in enhancing the impacts of activity on neurodegenerative disorders for future treatments. Research studies, both preclinical and clinical, that have documented the use of various exercises and their effects on ncRNAs and exosomal ncRNAs for the treatment of NDs have been compiled and enlisted from the PubMed database, spanning the time period from the year 2000 up to the current time. Studies show that manipulating specific ncRNAs or harnessing exercise-induced changes in ncRNA expression and exosomal cargo could potentially be utilized as therapeutic strategies for preventing or treating NDs. In conclusion, studies suggest that various exercise modalities, including aerobic, resistance, and high-intensity interval training, can modulate the expression of ncRNAs and exosomal ncRNAs in the context of NDs. The altered ncRNA profiles may contribute to the neuroprotective and therapeutic effects observed with exercise interventions. However, more research is needed to fully understand the underlying mechanisms and to further explore the potential of exercise-induced ncRNA signatures as biomarkers and therapeutic targets for neurodegenerative disorders.
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Affiliation(s)
- Shangwu Liu
- Department of Physical Education, Lyuliang University, Lishi, 033000, Shanxi, China
| | - Runhong Zhang
- Department of Physical Education, Lyuliang University, Lishi, 033000, Shanxi, China.
| | - Jamal Hallajzadeh
- Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran.
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Roy NS, Kumari M, Alam K, Bhattacharya A, Kaity S, Kaur K, Ravichandiran V, Roy S. Development of bioengineered 3D patient derived breast cancer organoid model focusing dynamic fibroblast-stem cell reciprocity. PROGRESS IN BIOMEDICAL ENGINEERING (BRISTOL, ENGLAND) 2024; 7:012007. [PMID: 39662055 DOI: 10.1088/2516-1091/ad9dcb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 12/11/2024] [Indexed: 12/13/2024]
Abstract
Three-dimensional (3D) models, such as tumor spheroids and organoids, are increasingly developed by integrating tissue engineering, regenerative medicine, and personalized therapy strategies. These advanced 3Din-vitromodels are not merely endpoint-driven but also offer the flexibility to be customized or modulated according to specific disease parameters. Unlike traditional 2D monolayer cultures, which inadequately capture the complexities of solid tumors, 3D co-culture systems provide a more accurate representation of the tumor microenvironment. This includes critical interactions with mesenchymal stem/stromal cells (MSCs) and induced pluripotent stem cells (iPSCs), which significantly modulate cancer cell behavior and therapeutic responses. Most of the findings from the co-culture of Michigan Cancer Foundation-7 breast cancer cells and MSC showed the formation of monolayers. Although changes in the plasticity of MSCs and iPSCs caused by other cells and extracellular matrix (ECM) have been extensively researched, the effect of MSCs on cancer stem cell (CSC) aggressiveness is still controversial and contradictory among different research communities. Some researchers have argued that CSCs proliferate more, while others have proposed that cancer spread occurs through dormancy. This highlights the need for further investigation into how these interactions shape cancer aggressiveness. The objective of this review is to explore changes in cancer cell behavior within a 3D microenvironment enriched with MSCs, iPSCs, and ECM components. By describing various MSC and iPSC-derived 3D breast cancer models that replicate tumor biology, we aim to elucidate potential therapeutic targets for breast cancer. A particular focus of this review is the Transwell system, which facilitates understanding how MSCs and iPSCs affect critical processes such as migration, invasion, and angiogenesis. The gradient formed between the two chambers is based on diffusion, as seen in the human body. Once optimized, this Transwell model can serve as a high-throughput screening platform for evaluating various anticancer agents. In the future, primary cell-based and patient-derived 3D organoid models hold promise for advancing personalized medicine and accelerating drug development processes.
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Affiliation(s)
- Nakka Sharmila Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Mamta Kumari
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Kamare Alam
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Anamitra Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Santanu Kaity
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Kulwinder Kaur
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine a Health Sciences, Dublin, Ireland
- Department of Anatomy & Regenerative Medicine, Tissue Engineering Research Group, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Velayutham Ravichandiran
- Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
| | - Subhadeep Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Chunilal Bhawan, 168 Maniktala Main Road, Kolkata, 700054 West Bengal, India
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Wu Y, Wagner WD. Syndecan-4 Functionalization Reduces the Thrombogenicity of Engineered Vascular Biomaterials. Ann Biomed Eng 2024; 52:1873-1882. [PMID: 37071281 PMCID: PMC11169030 DOI: 10.1007/s10439-023-03199-w] [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: 11/03/2022] [Accepted: 03/27/2023] [Indexed: 04/19/2023]
Abstract
Blood-biomaterial compatibility is essential for tissue repair especially for endovascular biomaterials where small-diameter vessel patency and endothelium formation is crucial. To address this issue, a composite biomaterial termed PFC fabricated from poly (glycerol sebacate), silk fibroin, and collagen was used to determine if functionalization with syndecan-4 (SYN4) would reduce thrombogenesis through the action of heparan sulfate. The material termed, PFC_SYN4, has structure and composition similar to native arterial tissue and has been reported to facilitate the binding and differentiation of endothelial colony-forming cells (ECFCs). In this study, the hemocompatibility of PFC_SYN4 was evaluated and compared with non-functionalized PFC, electrospun collagen, ePTFE, and bovine pericardial patch (BPV). Ultrastructurally, platelets were less activated when cultured on PFC and PFC_SYN4 compared to collagen where extensive platelet degranulation was observed. Quantitatively, 31% and 44% fewer platelets adhered to PFC_SYN4 compared to non-functionalized PFC and collagen, respectively. Functionalization of PFC resulted in reduced levels of complement activation compared to PFC, collagen, and BPV. Whole blood clotting times indicated that PFC_SYN4 was less thrombogenic compared with PFC, collagen, and BPV. These results suggest that syndecan-4 functionalization of blood-contacting biomaterials provides a novel solution for generating a reduced thrombogenic surface.
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Affiliation(s)
- Yidi Wu
- Department of Plastic & Reconstructive Surgery, Medical Center Boulevard, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
- Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem, NC, USA
| | - William D Wagner
- Department of Plastic & Reconstructive Surgery, Medical Center Boulevard, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
- Virginia Tech - Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem, NC, USA.
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC, USA.
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Vittum Z, Cocchiaro S, Mensah SA. Basal endothelial glycocalyx's response to shear stress: a review of structure, function, and clinical implications. Front Cell Dev Biol 2024; 12:1371769. [PMID: 38562144 PMCID: PMC10982814 DOI: 10.3389/fcell.2024.1371769] [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: 01/16/2024] [Accepted: 03/04/2024] [Indexed: 04/04/2024] Open
Abstract
The endothelial glycocalyx encompasses the entire endothelial cell, transducing extracellular signals and regulating vascular permeability and barrier functions. The apical glycocalyx, which forms the lumen of the vessel, and the basal glycocalyx, at the smooth muscle cell interface, are often investigated separately as they are exposed to vastly different stimuli. The apical glycocalyx directly senses fluid shear forces transmitting them intracellularly through connection to the cytoskeleton of the endothelial cell. The basal glycocalyx has demonstrated sensitivity to shear due to blood flow transmitted through the cytoskeleton, promoting alternate signaling processes. In this review, we discuss current literature on the basal glycocalyx's response to shear stress in the context of mechanotransduction and remodeling. The possible implications of basal glycocalyx degradation in pathologies are also explored. Finally, this review seeks to highlight how addressing the gaps discussed would improve our wholistic understanding of the endothelial glycocalyx and its role in maintaining vascular homeostasis.
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Affiliation(s)
- Zoe Vittum
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
| | - Samantha Cocchiaro
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
| | - Solomon A. Mensah
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
- Mechanical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
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Yang P, Lu Y, Gou W, Qin Y, Tan J, Luo G, Zhang Q. Glycosaminoglycans' Ability to Promote Wound Healing: From Native Living Macromolecules to Artificial Biomaterials. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305918. [PMID: 38072674 PMCID: PMC10916610 DOI: 10.1002/advs.202305918] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/25/2023] [Indexed: 03/07/2024]
Abstract
Glycosaminoglycans (GAGs) are important for the occurrence of signaling molecules and maintenance of microenvironment within the extracellular matrix (ECM) in living tissues. GAGs and GAG-based biomaterial approaches have been widely explored to promote in situ tissue regeneration and repair by regulating the wound microenvironment, accelerating re-epithelialization, and controlling ECM remodeling. However, most approaches remain unacceptable for clinical applications. To improve insights into material design and clinical translational applications, this review highlights the innate roles and bioactive mechanisms of native GAGs during in situ wound healing and presents common GAG-based biomaterials and the adaptability of application scenarios in facilitating wound healing. Furthermore, challenges before the widespread commercialization of GAG-based biomaterials are shared, to ensure that future designed and constructed GAG-based artificial biomaterials are more likely to recapitulate the unique and tissue-specific profile of native GAG expression in human tissues. This review provides a more explicit and clear selection guide for researchers designing biomimetic materials, which will resemble or exceed their natural counterparts in certain functions, thereby suiting for specific environments or therapeutic goals.
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Affiliation(s)
- Peng Yang
- Institute of Burn ResearchState Key Laboratory of TraumaBurn and Combined InjurySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Yifei Lu
- Institute of Burn ResearchState Key Laboratory of TraumaBurn and Combined InjurySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Weiming Gou
- Institute of Burn ResearchState Key Laboratory of TraumaBurn and Combined InjurySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Yiming Qin
- Department of Dermatology and Laboratory of DermatologyClinical Institute of Inflammation and ImmunologyFrontiers Science Center for Disease‐Related Molecular NetworkWest China HospitalSichuan UniversityChengdu610041China
| | - Jianglin Tan
- Institute of Burn ResearchState Key Laboratory of TraumaBurn and Combined InjurySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Gaoxing Luo
- Institute of Burn ResearchState Key Laboratory of TraumaBurn and Combined InjurySouthwest HospitalThird Military Medical UniversityChongqing400038China
| | - Qing Zhang
- Institute of Burn ResearchState Key Laboratory of TraumaBurn and Combined InjurySouthwest HospitalThird Military Medical UniversityChongqing400038China
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Sao K, Risbud MV. Proteoglycan Dysfunction: A Common Link Between Intervertebral Disc Degeneration and Skeletal Dysplasia. Neurospine 2024; 21:162-178. [PMID: 38569642 PMCID: PMC10992626 DOI: 10.14245/ns.2347342.671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/04/2024] [Accepted: 02/23/2024] [Indexed: 04/05/2024] Open
Abstract
Proteoglycans through their sulfated glycosaminoglycans regulate cell-matrix signaling during tissue development, regeneration, and degeneration processes. Large extracellular proteoglycans such as aggrecan, versican, and perlecan are especially important for the structural integrity of the intervertebral disc and cartilage during development. In these tissues, proteoglycans are responsible for hydration, joint flexibility, and the absorption of mechanical loads. Loss or reduction of these molecules can lead to disc degeneration and skeletal dysplasia, evident from loss of disc height or defects in skeletal development respectively. In this review, we discuss the common proteoglycans found in the disc and cartilage and elaborate on various murine models and skeletal dysplasias in humans to highlight how their absence and/or aberrant expression causes accelerated disc degeneration and developmental defects.
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Affiliation(s)
- Kimheak Sao
- Graduate Program in Cell Biology and Regenerative Medicine, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Makarand V. Risbud
- Graduate Program in Cell Biology and Regenerative Medicine, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
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Ma M, Zhuang J, Li H, Mi R, Song Y, Yang W, Lu Y, Shen X, Wu Y, Shen H. Low expression of ZFP36L1 in osteosarcoma promotes lung metastasis by inhibiting the SDC4-TGF-β signaling feedback loop. Oncogene 2024; 43:47-60. [PMID: 37935976 PMCID: PMC10766520 DOI: 10.1038/s41388-023-02880-7] [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: 06/24/2023] [Revised: 10/17/2023] [Accepted: 10/23/2023] [Indexed: 11/09/2023]
Abstract
ZFP36L1, which is a negative regulator of gene transcripts, has been proven to regulate the progression of several carcinomas. However, its role in sarcoma remains unknown. Here, by using data analyses and in vivo experiments, we found that ZFP36L1 inhibited the lung metastasis of osteosarcoma (OS). Knockdown of ZFP36L1 promoted OS cell migration by activating TGF-β signaling and increasing SDC4 expression. Intriguingly, we observed a positive feedback loop between SDC4 and TGF-β signaling. SDC4 protected TGFBR3 from matrix metalloproteinase (MMP)-mediated cleavage and therefore relieved the inhibition of TGF-β signaling by soluble TGFBR3, while TGF-β signaling positively regulated SDC4 transcription. We also proved that ZFP36L1 regulated SDC4 mRNA decay through adenylate-uridylate (AU)-rich elements (AREs) in its 3'UTR. Furthermore, treatment with SB431542 (a TGF-β receptor kinase inhibitor) and MK2 inhibitor III (a MAPKAPK2 inhibitor that increases the ability of ZFP36L1 to degrade mRNA) dramatically inhibited OS lung metastasis, suggesting a promising therapeutic approach for the treatment of OS lung metastasis.
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Affiliation(s)
- Mengjun Ma
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Jiahao Zhuang
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Hongyu Li
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Rujia Mi
- Center for Biotherapy, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Yihui Song
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Wen Yang
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Yixuan Lu
- Center for Biotherapy, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Xin Shen
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Yanfeng Wu
- Center for Biotherapy, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China.
| | - Huiyong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China.
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Rodríguez-Franco HJ, Weiden J, Bastings MMC. Stabilizing Polymer Coatings Alter the Protein Corona of DNA Origami and Can Be Engineered to Bias the Cellular Uptake. ACS POLYMERS AU 2023; 3:344-353. [PMID: 37576710 PMCID: PMC10416322 DOI: 10.1021/acspolymersau.3c00009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 08/15/2023]
Abstract
With DNA-based nanomaterials being designed for applications in cellular environments, the need arises to accurately understand their surface interactions toward biological targets. As for any material exposed to protein-rich cell culture conditions, a protein corona will establish around DNA nanoparticles, potentially altering the a-priori designed particle function. Here, we first set out to identify the protein corona around DNA origami nanomaterials, taking into account the application of stabilizing block co-polymer coatings (oligolysine-1kPEG or oligolysine-5kPEG) widely used to ensure particle integrity. By implementing a label-free methodology, the distinct polymer coating conditions show unique protein profiles, predominantly defined by differences in the molecular weight and isoelectric point of the adsorbed proteins. Interestingly, none of the applied coatings reduced the diversity of the proteins detected within the specific coronae. We then biased the protein corona through pre-incubation with selected proteins and show significant changes in the cell uptake. Our study contributes to a deeper understanding of the complex interplay between DNA nanomaterials, proteins, and cells at the bio-interface.
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Affiliation(s)
- Hugo J. Rodríguez-Franco
- Programmable Biomaterials Laboratory,
Institute of Materials, Interfaculty Bioengineering Institute, School
of Engineering, Ecole Polytechnique Fédérale
Lausanne, Lausanne 1015, Switzerland
| | - Jorieke Weiden
- Programmable Biomaterials Laboratory,
Institute of Materials, Interfaculty Bioengineering Institute, School
of Engineering, Ecole Polytechnique Fédérale
Lausanne, Lausanne 1015, Switzerland
| | - Maartje M. C. Bastings
- Programmable Biomaterials Laboratory,
Institute of Materials, Interfaculty Bioengineering Institute, School
of Engineering, Ecole Polytechnique Fédérale
Lausanne, Lausanne 1015, Switzerland
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12
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Heras‐Parets A, Ginebra M, Manero JM, Guillem‐Marti J. Guiding Fibroblast Activation Using an RGD-Mutated Heparin Binding II Fragment of Fibronectin for Gingival Titanium Integration. Adv Healthc Mater 2023; 12:e2203307. [PMID: 37100430 PMCID: PMC11468578 DOI: 10.1002/adhm.202203307] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 03/15/2023] [Indexed: 04/28/2023]
Abstract
The formation of a biological seal around the neck of titanium (Ti) implants is critical for ensuring integration at the gingival site and for preventing bacterial colonization that may lead to periimplantitis. This process is guided by activated fibroblasts, named myofibroblasts, which secrete extracellular matrix (ECM) proteins and ECM-degrading enzymes resolving the wound. However, in some cases, Ti is not able to attract and activate fibroblasts to a sufficient extent, which may compromise the success of the implant. Fibronectin (FN) is an ECM component found in wounds that is able to guide soft tissue healing through the adhesion of cells and attraction of growth factors (GFs). However, clinical use of FN functionalized Ti implants is problematic because FN is difficult to obtain, and is sensitive to degradation. Herein, functionalizing Ti with a modified recombinant heparin binding II (HBII) domain of FN, mutated to include an Arg-Gly-Asp (RGD) sequence for promoting both fibroblast adhesion and GF attraction, is aimed at. The HBII-RGD domain is able to stimulate fibroblast adhesion, spreading, proliferation, migration, and activation to a greater extent than the native HBII, reaching values closer to those of full-length FN suggesting that it might induce the formation of a biological sealing.
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Affiliation(s)
- Aina Heras‐Parets
- BiomaterialsBiomechanics and Tissue Engineering groupDepartment of Materials Science and EngineeringUniversitat Politècnica de Catalunya – BarcelonaTech (UPC)Av. Eduard Maristany 16Barcelona08930Spain
- Barcelona Research Center in Multiscale Science and EngineeringUPCAv. Eduard Maristany 16Barcelona08930Spain
| | - Maria‐Pau Ginebra
- BiomaterialsBiomechanics and Tissue Engineering groupDepartment of Materials Science and EngineeringUniversitat Politècnica de Catalunya – BarcelonaTech (UPC)Av. Eduard Maristany 16Barcelona08930Spain
- Barcelona Research Center in Multiscale Science and EngineeringUPCAv. Eduard Maristany 16Barcelona08930Spain
- Institute for Bioengineering of Catalonia (IBEC)Barcelona Institute of Science and Technology (BIST)Barcelona08028Spain
| | - Jose Maria Manero
- BiomaterialsBiomechanics and Tissue Engineering groupDepartment of Materials Science and EngineeringUniversitat Politècnica de Catalunya – BarcelonaTech (UPC)Av. Eduard Maristany 16Barcelona08930Spain
- Barcelona Research Center in Multiscale Science and EngineeringUPCAv. Eduard Maristany 16Barcelona08930Spain
| | - Jordi Guillem‐Marti
- BiomaterialsBiomechanics and Tissue Engineering groupDepartment of Materials Science and EngineeringUniversitat Politècnica de Catalunya – BarcelonaTech (UPC)Av. Eduard Maristany 16Barcelona08930Spain
- Barcelona Research Center in Multiscale Science and EngineeringUPCAv. Eduard Maristany 16Barcelona08930Spain
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13
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Maldonado H, Leyton L. CSK-mediated signalling by integrins in cancer. Front Cell Dev Biol 2023; 11:1214787. [PMID: 37519303 PMCID: PMC10382208 DOI: 10.3389/fcell.2023.1214787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 06/19/2023] [Indexed: 08/01/2023] Open
Abstract
Cancer progression and metastasis are processes heavily controlled by the integrin receptor family. Integrins are cell adhesion molecules that constitute the central components of mechanosensing complexes called focal adhesions, which connect the extracellular environment with the cell interior. Focal adhesions act as key players in cancer progression by regulating biological processes, such as cell migration, invasion, proliferation, and survival. Src family kinases (SFKs) can interplay with integrins and their downstream effectors. SFKs also integrate extracellular cues sensed by integrins and growth factor receptors (GFR), transducing them to coordinate metastasis and cell survival in cancer. The non-receptor tyrosine kinase CSK is a well-known SFK member that suppresses SFK activity by phosphorylating its specific negative regulatory loop (C-terminal Y527 residue). Consequently, CSK may play a pivotal role in tumour progression and suppression by inhibiting SFK oncogenic effects in several cancer types. Remarkably, CSK can localise near focal adhesions when SFKs are activated and even interact with focal adhesion components, such as phosphorylated FAK and Paxillin, among others, suggesting that CSK may regulate focal adhesion dynamics and structure. Even though SFK oncogenic signalling has been extensively described before, the specific role of CSK and its crosstalk with integrins in cancer progression, for example, in mechanosensing, remain veiled. Here, we review how CSK, by regulating SFKs, can regulate integrin signalling, and focus on recent discoveries of mechanotransduction. We additionally examine the cross talk of integrins and GFR as well as the membrane availability of these receptors in cancer. We also explore new pharmaceutical approaches to these signalling pathways and analyse them as future therapeutic targets.
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Affiliation(s)
- Horacio Maldonado
- Receptor Dynamics in Cancer Laboratory, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Lisette Leyton
- Cellular Communication Laboratory, Programa de Biología Celular y Molecular, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile, Santiago, Chile
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14
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Vuorinen SI, Okolicsanyi RK, Gyimesi M, Meyjes-Brown J, Saini D, Pham SH, Griffiths LR, Haupt LM. SDC4-rs1981429 and ATM-rs228590 may provide early biomarkers of breast cancer risk. J Cancer Res Clin Oncol 2023; 149:4563-4578. [PMID: 36152082 PMCID: PMC10349731 DOI: 10.1007/s00432-022-04236-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 07/23/2022] [Indexed: 01/20/2023]
Abstract
In Australia, 13% of women are diagnosed with breast cancer (BC) in their lifetime with approximately 20,000 women diagnosed with the disease in 2021. BC is characterised by complex histological and genomic influences with recent advances in cancer biology improving early diagnosis and personalised treatment interventions. The Phosphatidyl-inositol-3-kinase/Protein kinase B (PI3K/AKT) pathway is essential in apoptosis resistance, cell survival, activation of cellular responses to DNA damage and DNA repair. Heparan sulfate proteoglycans (HSPGs) are ubiquitous molecules found on the cell surface and in the extracellular matrix with essential functions in regulating cell survival, growth, adhesion and as mediators of cell differentiation and migration. HSPGs, particularly the syndecans (SDCs), have been linked to cancers, making them an exciting target for anticancer treatments. In the PI3K/AKT pathway, syndecan-4 (SDC4) has been shown to downregulate AKT Serine/Threonine Kinase (AKT1) gene expression, while the ATM Serine/Threonine Kinase (ATM) gene has been found to inhibit this pathway upstream of AKT. We investigated single-nucleotide polymorphisms (SNPs) in HSPG and related genes SDC4, AKT1 and ATM and their influence on the prevalence of BC. SNPs were genotyped in the Australian Caucasian Genomics Research Centre Breast Cancer (GRC-BC) population and in the Griffith University-Cancer Council Queensland Breast Cancer Biobank (GU-CCQ BB) population. We identified that SDC4-rs1981429 and ATM-rs228590 may influence the development and progression of BC, having the potential to become biomarkers in early BC diagnosis and personalised treatment.
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Affiliation(s)
- Sofia I Vuorinen
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia
| | - Rachel K Okolicsanyi
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia
| | - Martina Gyimesi
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia
| | - Jacob Meyjes-Brown
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia
| | - Deepa Saini
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia
| | - Son H Pham
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia
| | - Lyn R Griffiths
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia
| | - Larisa M Haupt
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia.
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15
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Chen J, Sun T, You Y, Lin B, Wu B, Wu J. Genome-wide identification of potential odontogenic genes involved in the dental epithelium-mesenchymal interaction during early odontogenesis. BMC Genomics 2023; 24:163. [PMID: 37013486 PMCID: PMC10069120 DOI: 10.1186/s12864-023-09140-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 01/16/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Epithelium-mesenchymal interactions are involved in odontogenic processes. Previous studies have focused on the intracellular signalling regulatory network in tooth development, but the functions of extracellular regulatory molecules have remained unclear. This study aims to explore the gene profile of extracellular proteoglycans and their glycosaminoglycan chains potentially involved in dental epithelium-mesenchymal interactions using high-throughput sequencing to provide new understanding of early odontogenesis. RESULTS Whole transcriptome profiles of the mouse dental epithelium and mesenchyme were investigated by RNA sequencing (RNA-seq). A total of 1,281 and 1,582 differentially expressed genes were identified between the dental epithelium and mesenchyme at E11.5 and E13.5, respectively. Enrichment analysis showed that extracellular regions and ECM-receptor interactions were significantly enriched at both E11.5 and E13.5. Polymerase chain reaction analysis confirmed that the extracellular proteoglycan family exhibited distinct changes during epithelium-mesenchymal interactions. Most proteoglycans showed higher transcript levels in the dental mesenchyme, whereas only a few were upregulated in the epithelium at both stages. In addition, 9 proteoglycans showed dynamic expression changes between these two tissue compartments. Gpc4, Sdc2, Spock2, Dcn and Lum were expressed at higher levels in the dental epithelium at E11.5, whereas their expression was significantly higher in the dental mesenchyme at E13.5, which coincides with the odontogenic potential shift. Moreover, the glycosaminoglycan biosynthetic enzymes Ext1, Hs3st1/5, Hs6st2/3, Ndst3 and Sulf1 also exhibited early upregulation in the epithelium but showed markedly higher expression in the mesenchyme after the odontogenic potential shift. CONCLUSION This study reveals the dynamic expression profile of extracellular proteoglycans and their biosynthetic enzymes during the dental epithelium-mesenchymal interaction. This study offers new insight into the roles of extracellular proteoglycans and their distinct sulfation underlying early odontogenesis.
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Affiliation(s)
- Jiawen Chen
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- School of Stomatology, Southern Medical University, Guangzhou, 510515, China
| | - Tianyu Sun
- Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Yan You
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- School of Stomatology, Southern Medical University, Guangzhou, 510515, China
| | - Binbin Lin
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- School of Stomatology, Southern Medical University, Guangzhou, 510515, China
| | - Buling Wu
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- School of Stomatology, Southern Medical University, Guangzhou, 510515, China.
- Southern Medical University- Shenzhen Stomatology Hospital (Pingshan), ShenZhen, 518118, China.
| | - Jingyi Wu
- Center of Oral Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, 510280, China.
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16
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Hübers C, Abdul Pari AA, Grieshober D, Petkov M, Schmidt A, Messmer T, Heyer CM, Schölch S, Kapel SS, Gengenbacher N, Singhal M, Schieb B, Fricke C, Will R, Remans K, Utikal JS, Reissfelder C, Schlesner M, Hodivala-Dilke KM, Kersten S, Goerdt S, Augustin HG, Felcht M. Primary tumor-derived systemic nANGPTL4 inhibits metastasis. J Exp Med 2023; 220:e20202595. [PMID: 36269299 PMCID: PMC9595206 DOI: 10.1084/jem.20202595] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 08/07/2022] [Accepted: 09/15/2022] [Indexed: 11/04/2022] Open
Abstract
Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.
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Affiliation(s)
- Corinne Hübers
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University and Centre of Excellence of Dermatology of Baden-Württemberg, Mannheim, Germany
| | - Ashik Ahmed Abdul Pari
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Denise Grieshober
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Martin Petkov
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | | | - Tatjana Messmer
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University and Centre of Excellence of Dermatology of Baden-Württemberg, Mannheim, Germany
| | - Christian Moritz Heyer
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, Augsburg, Germany
| | - Sebastian Schölch
- JCCU Translational Surgical Oncology (A430), German Cancer Research Center, Heidelberg, Germany
- Department of Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ-Hector Cancer Institute at University Medical Centre Mannheim, Mannheim, Germany
| | - Stephanie S. Kapel
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Nicolas Gengenbacher
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Mahak Singhal
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
- Laboratory of AngioRhythms, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Benjamin Schieb
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Claudine Fricke
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Rainer Will
- Genomics & Proteomics Core Facilities, German Cancer Research Center, Heidelberg, Germany
| | - Kim Remans
- Protein Expression and Purification Core Facility, European Molecular Biology Center, Heidelberg, Germany
| | - Jochen Sven Utikal
- Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University and Centre of Excellence of Dermatology of Baden-Württemberg, Mannheim, Germany
- Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany
| | - Christoph Reissfelder
- Department of Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ-Hector Cancer Institute at University Medical Centre Mannheim, Mannheim, Germany
| | - Matthias Schlesner
- Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, Augsburg, Germany
| | - Kairbaan M. Hodivala-Dilke
- Center for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Center, London, United Kingdom
| | - Sander Kersten
- Nutrition, Metabolism and Genomics group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Sergij Goerdt
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University and Centre of Excellence of Dermatology of Baden-Württemberg, Mannheim, Germany
| | - Hellmut G. Augustin
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Moritz Felcht
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergy, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University and Centre of Excellence of Dermatology of Baden-Württemberg, Mannheim, Germany
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17
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Katsuki S, K. Jha P, Lupieri A, Nakano T, Passos LS, Rogers MA, Becker-Greene D, Le TD, Decano JL, Ho Lee L, Guimaraes GC, Abdelhamid I, Halu A, Muscoloni A, V. Cannistraci C, Higashi H, Zhang H, Vromman A, Libby P, Keith Ozaki C, Sharma A, Singh SA, Aikawa E, Aikawa M. Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms. Circ Res 2022; 131:873-889. [PMID: 36263780 PMCID: PMC9973449 DOI: 10.1161/circresaha.121.320056] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. METHODS We used Ldlr-/- mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr-/- mouse macrophages. RESULTS In Ldlr-/- mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1β (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr-/- mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages. CONCLUSIONS Circulating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need.
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Affiliation(s)
- Shunsuke Katsuki
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Prabhash K. Jha
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Adrien Lupieri
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Toshiaki Nakano
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Livia S.A. Passos
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Maximillian A. Rogers
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Dakota Becker-Greene
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Thanh-Dat Le
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Julius L. Decano
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Lang Ho Lee
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Gabriel C. Guimaraes
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Ilyes Abdelhamid
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
- Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Arda Halu
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
- Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Alessandro Muscoloni
- The Biomedical Cybernetics Group, Biotechnology Center, Center for Molecular and Cellular Bioengineering, Center for Systems Biology Dresden, Cluster of Excellence Physics of Life, Department of Physics, Technical University Dresden, Dresden, Germany (A.M., C.V.C)
- Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.)
| | - Carlo V. Cannistraci
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
- Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.)
| | - Hideyuki Higashi
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Hengmin Zhang
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Amélie Vromman
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Peter Libby
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - C. Keith Ozaki
- Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.)
| | - Amitabh Sharma
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
- Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Sasha A. Singh
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Elena Aikawa
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Masanori Aikawa
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
- Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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18
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Takahashi I. Importance of Heparan Sulfate Proteoglycans in Pancreatic Islets and β-Cells. Int J Mol Sci 2022; 23:12082. [PMID: 36292936 PMCID: PMC9603760 DOI: 10.3390/ijms232012082] [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: 09/01/2022] [Accepted: 09/20/2022] [Indexed: 12/15/2022] Open
Abstract
β-cells in the islets of Langerhans of the pancreas secrete insulin in response to the glucose concentration in the blood. When these pancreatic β-cells are damaged, diabetes develops through glucose intolerance caused by insufficient insulin secretion. High molecular weight polysaccharides, such as heparin and heparan sulfate (HS) proteoglycans, and HS-degrading enzymes, such as heparinase, participate in the protection, maintenance, and enhancement of the functions of pancreatic islets and β-cells, and the demand for studies on glycobiology within the field of diabetes research has increased. This review introduces the roles of complex glycoconjugates containing high molecular weight polysaccharides and their degrading enzymes in pancreatic islets and β-cells, including those obtained in studies conducted by us earlier. In addition, from the perspective of glycobiology, this study proposes the possibility of application to diabetes medicine.
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Affiliation(s)
- Iwao Takahashi
- Division of Molecular and Cellular Pharmacology, Department of Pathophysiology and Pharmacology, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Morioka 028-3694, Iwate, Japan
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19
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Donato L, Scimone C, Alibrandi S, Scalinci SZ, Rinaldi C, D’Angelo R, Sidoti A. Epitranscriptome Analysis of Oxidative Stressed Retinal Epithelial Cells Depicted a Possible RNA Editing Landscape of Retinal Degeneration. Antioxidants (Basel) 2022; 11:antiox11101967. [PMID: 36290689 PMCID: PMC9598096 DOI: 10.3390/antiox11101967] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
Oxidative stress represents one of the principal causes of inherited retinal dystrophies, with many related molecular mechanisms still unknown. We investigated the posttranscriptional RNA editing landscape of human retinal pigment epithelium cells (RPE) exposed to the oxidant agent N-retinylidene-N-retinyl ethanolamine (A2E) for 1 h, 2 h, 3 h and 6 h. Using a transcriptomic approach, refined with a specific multialgorithm pipeline, 62,880 already annotated and de novo RNA editing sites within about 3000 genes were identified among all samples. Approximately 19% of these RNA editing sites were found within 3' UTR, including sites common to all time points that were predicted to change the binding capacity of 359 miRNAs towards 9654 target genes. A2E exposure also determined significant gene expression differences in deaminase family ADAR, APOBEC and ADAT members, involved in canonical and tRNA editing events. On GO and KEGG enrichment analyses, genes that showed different RNA editing levels are mainly involved in pathways strongly linked to a possible neovascularization of retinal tissue, with induced apoptosis mediated by the ECM and surface protein altered signaling. Collectively, this work demonstrated dynamic RNA editome profiles in RPE cells for the first time and shed more light on new mechanisms at the basis of retinal degeneration.
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Affiliation(s)
- Luigi Donato
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy
- Department of Biomolecular Strategies, Genetics and Cutting-Edge Therapies, I.E.ME.S.T., 90139 Palermo, Italy
| | - Concetta Scimone
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy
- Department of Biomolecular Strategies, Genetics and Cutting-Edge Therapies, I.E.ME.S.T., 90139 Palermo, Italy
| | - Simona Alibrandi
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy
- Department of Biomolecular Strategies, Genetics and Cutting-Edge Therapies, I.E.ME.S.T., 90139 Palermo, Italy
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98125 Messina, Italy
- Correspondence: ; Tel.: +39-090-221-3136
| | - Sergio Zaccaria Scalinci
- DIMEC (Department of Medical and Surgical Sciences), University of Bologna, 40121 Bologna, Italy
| | - Carmela Rinaldi
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy
| | - Rosalia D’Angelo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy
| | - Antonina Sidoti
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy
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20
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Støle TP, Lunde M, Shen X, Martinsen M, Lunde PK, Li J, Lockwood F, Sjaastad I, Louch WE, Aronsen JM, Christensen G, Carlson CR. The female syndecan-4−/− heart has smaller cardiomyocytes, augmented insulin/pSer473-Akt/pSer9-GSK-3β signaling, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels. Front Cell Dev Biol 2022; 10:908126. [PMID: 36092718 PMCID: PMC9452846 DOI: 10.3389/fcell.2022.908126] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Background: In cardiac muscle, the ubiquitously expressed proteoglycan syndecan-4 is involved in the hypertrophic response to pressure overload. Protein kinase Akt signaling, which is known to regulate hypertrophy, has been found to be reduced in the cardiac muscle of exercised male syndecan-4−/− mice. In contrast, we have recently found that pSer473-Akt signaling is elevated in the skeletal muscle (tibialis anterior, TA) of female syndecan-4−/− mice. To determine if the differences seen in Akt signaling are sex specific, we have presently investigated Akt signaling in the cardiac muscle of sedentary and exercised female syndecan-4−/− mice. To get deeper insight into the female syndecan-4−/− heart, alterations in cardiomyocyte size, a wide variety of different extracellular matrix components, well-known syndecan-4 binding partners and associated signaling pathways have also been investigated.Methods: Left ventricles (LVs) from sedentary and exercise trained female syndecan-4−/− and WT mice were analyzed by immunoblotting and real-time PCR. Cardiomyocyte size and phosphorylated Ser473-Akt were analyzed in isolated adult cardiomyocytes from female syndecan-4−/− and WT mice by confocal imaging. LV and skeletal muscle (TA) from sedentary male syndecan-4−/− and WT mice were immunoblotted with Akt antibodies for comparison. Glucose levels were measured by a glucometer, and fasting blood serum insulin and C-peptide levels were measured by ELISA.Results: Compared to female WT hearts, sedentary female syndecan-4−/− LV cardiomyocytes were smaller and hearts had higher levels of pSer473-Akt and its downstream target pSer9-GSK-3β. The pSer473-Akt inhibitory phosphatase PHLPP1/SCOP was lowered, which may be in response to the elevated serum insulin levels found in the female syndecan-4−/− mice. We also observed lowered levels of pThr308-Akt/Akt and GLUT4 in the female syndecan-4−/− heart and an increased LRP6 level after exercise. Otherwise, few alterations were found. The pThr308-Akt and pSer473-Akt levels were unaltered in the cardiac and skeletal muscles of sedentary male syndecan-4−/− mice.Conclusion: Our data indicate smaller cardiomyocytes, an elevated insulin/pSer473-Akt/pSer9-GSK-3β signaling pathway, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels in the female syndecan-4−/− heart. In contrast, cardiomyocyte size, and Akt signaling were unaltered in both cardiac and skeletal muscles from male syndecan-4−/− mice, suggesting important sex differences.
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Affiliation(s)
- Thea Parsberg Støle
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- *Correspondence: Thea Parsberg Støle,
| | - Marianne Lunde
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Xin Shen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Marita Martinsen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Per Kristian Lunde
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Jia Li
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Francesca Lockwood
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Ivar Sjaastad
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - William Edward Louch
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Jan Magnus Aronsen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Geir Christensen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
- K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Cathrine Rein Carlson
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
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21
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Wu J, Li X, Wang Q, Wang S, He W, Wu Q, Dong C. LncRNA/miRNA/mRNA ceRNA network analysis in spinal cord injury rat with physical exercise therapy. PeerJ 2022; 10:e13783. [PMID: 35923891 PMCID: PMC9341448 DOI: 10.7717/peerj.13783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 07/05/2022] [Indexed: 01/22/2023] Open
Abstract
Noncoding RNAs have been implicated in the pathophysiology of spinal cord injury (SCI), including cell death, glial scar formation, axonal collapse and demyelination, and inflammation. The evidence suggests that exercise therapy is just as effective as medical treatment in SCI. However, studies of competing endogenous RNA (ceRNA)-mediated regulation mechanisms in the therapy of SCI with exercise are rare. The focus of this research was to investigate the effect of exercise therapy on the expression levels of long noncoding RNA (lncRNA), microRNA (miRNA), and mRNA in rats with SCI. The RNA-seq technology has been used to examine the differentially expressed circRNAs (DECs), lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs) between SCI and exercise therapy rats. The ceRNA network was established using interactions between miRNAs and mRNAs, as well as between miRNAs and lncRNAs/circRNAs. The Database for Annotation, Visualization, and Integrated Discovery was used to anticipate the underlying functions of mRNAs. Our current study identified 76 DELs, 33 DEMs, and 30 DEGs between groups of SCI rats and exercise therapy rats. Subsequently, these newly discovered ceRNA interaction axes could be important targets for the exercise treatment of SCI.
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Affiliation(s)
- Jiahuan Wu
- Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Rehabilitation Medical Center, Suzhou, China
| | - Xiangzhe Li
- Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Rehabilitation Medical Center, Suzhou, China
| | - Qinghua Wang
- Nantong University, Experimental Animal Center, Nantong, China
| | - Sheng Wang
- Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Rehabilitation Medical Center, Suzhou, China
| | - Wenhua He
- Medical College of Nantong University, Department of Anatomy, Nantong, China
| | - Qinfeng Wu
- Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Rehabilitation Medical Center, Suzhou, China
| | - Chuanming Dong
- Medical College of Nantong University, Department of Anatomy, Nantong, China
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22
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Wu J, Wu D, Wu G, Bei HP, Li Z, Xu H, Wang Y, Wu D, Liu H, Shi S, Zhao C, Xu Y, He Y, Li J, Wang C, Zhao X, Wang S. Scale-out production of extracellular vesicles derived from natural killer cells via mechanical stimulation in a seesaw-motion bioreactor for cancer therapy. Biofabrication 2022; 14. [PMID: 35793612 DOI: 10.1088/1758-5090/ac7eeb] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 07/06/2022] [Indexed: 11/11/2022]
Abstract
Extracellular vesicles (EVs) derived from immune cells have shown great anti-cancer therapeutic potential. However, inefficiency in EV generation has considerably impeded the development of EV-based basic research and clinical translation. Here, we developed a seesaw-motion bioreactor (SMB) system by leveraging mechanical stimuli such as shear stress and turbulence for generating EVs with high quality and quantity from natural killer (NK) cells. Compared to EV production in traditional static culture (229 ± 74 particles per cell per day), SMB produced NK-92MI-derived EVs at a higher rate of 438 ± 50 particles per cell per day and yielded a total number of 2 × 1011 EVs over two weeks via continuous dynamic fluidic culture. In addition, the EVs generated from NK-92MI cells in SMB shared a similar morphology, size distribution, and protein profile to EVs generated from traditional static culture. Most importantly, the NK-92MI-derived EVs in SMB were functionally active in killing melanoma and liver cancer cells in both 2D and 3D culture conditions in vitro, as well as in suppressing melanoma growth in vivo. We believe that SMB is an attractive approach to producing EVs with high quality and quantity; it can additionally enhance EV production from NK92-MI cells and promote both the basic and translational research of EVs.
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Affiliation(s)
- Jianguo Wu
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Di Wu
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Guohua Wu
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Ho-Pan Bei
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, 11 Yuk Choi Rd, Hung Hom, Hong Kong, Hong Kong SAR, HONG KONG
| | - Zihan Li
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Han Xu
- Department of Building Environment and Energy Engineering, Xi'an Jiaotong University, 28 Xianning W Rd, Beilin, Xi'An, Shaanxi, China, 710049, Xi'an, Shanxi Province, 710049, CHINA
| | - Yimin Wang
- Institute of Translational Medicine, Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, HangZhou, 310027, CHINA
| | - Dan Wu
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Hui Liu
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Shengyu Shi
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Chao Zhao
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, The Old Schools, Trinity Ln, Cambridge CB2 1TN, United Kingdom, Cambridge, CB2 1TN, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
| | - Yibing Xu
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Yong He
- Department of Mechanical Engineering, Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, ZheJiang, 310027, CHINA
| | - Jun Li
- Zhejiang University, 866 Yuhangtang Rd, Xihu, Hangzhou, Zhejiang, China, 310027, Hangzhou, Zhejiang Province, 310058, CHINA
| | - Changyong Wang
- Department of Neural Engineering and Biological Interdisciplinary Studies, Institude of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Academy of Military Medical Sciences, Taiping Rd. 27, 100850, Tianjin, Beijing, China, Beijing, 100850, CHINA
| | - Xin Zhao
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, 11 Yuk Choi Rd, Hung Hom, Hong Kong, Hong Kong SAR, 999077, HONG KONG
| | - Shuqi Wang
- Sichuan University, 252 Shuncheng Ave, Qingyang District, Chengdu, Sichuan, China, Chengdu, Sichuan, 610017, CHINA
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23
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Cui C, Pan Y, Zhang C, Zhu D, Xuan Y, Hao P, Ke X, Zhou X, Qu Y. Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells. Am J Cancer Res 2022; 12:2697-2710. [PMID: 35812066 PMCID: PMC9251693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/07/2022] [Indexed: 06/15/2023] Open
Abstract
Syndecan-4 (SDC4) is a single-pass transmembrane glycoprotein implicated in a variety of oncogenic signaling pathways. It is also an intrinsically disordered protein and considered "undruggable". In the present study, we confirmed that knocking out SDC4 in pancreatic cancer cells markedly impaired macropinocytosis, colony formation, as well as xenograft tumor initiation and growth. Quantitative proteomic profiling of Sdc4 knockout (KO) cells revealed significant changes in cell metabolic pathways. In a cellular protein-based ligand interaction screening, we identified that Eltrombopag (ETBP), an FDA-approved agonist of the thrombopoietin receptor (TPOR) for immune thrombocytopenia, could directly bind to SDC4 with a Kd value of ~2 µM. We showed that the transmembrane motif was essential for SDC4 binding to ETBP. Unexpectedly, ETBP not only increased SDC4 abundance, but also enhanced SDC4-associated MAPK signaling pathway and macropinocytosis in cancer cells. Our results indicate that ETBP is a potential agonist of SDC4 in a fashion similar to its original target TPOR, and that caution should be taken when using ETBP for chemotherapy-induced thrombocytopenia in cancer patients.
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Affiliation(s)
- Can Cui
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Yuting Pan
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Chengqian Zhang
- School of Life Science and Technology, ShanghaiTech UniversityShanghai, China
| | - Darong Zhu
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Ying Xuan
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Piliang Hao
- School of Life Science and Technology, ShanghaiTech UniversityShanghai, China
| | - Xisong Ke
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Xianglian Zhou
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
| | - Yi Qu
- Center for Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai, China
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24
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Hu P, Leyton L, Hagood JS, Barker TH. Thy-1-Integrin Interactions in cis and Trans Mediate Distinctive Signaling. Front Cell Dev Biol 2022; 10:928510. [PMID: 35733855 PMCID: PMC9208718 DOI: 10.3389/fcell.2022.928510] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 05/23/2022] [Indexed: 12/04/2022] Open
Abstract
Thy-1 is a cell surface glycosylphosphatidylinositol (GPI)-anchored glycoprotein that bears a broad mosaic of biological roles across various cell types. Thy-1 displays strong physiological and pathological implications in development, cancer, immunity, and tissue fibrosis. Quite uniquely, Thy-1 is capable of mediating integrin-related signaling through direct trans- and cis-interaction with integrins. Both interaction types have shown distinctive roles, even when interacting with the same type of integrin, where binding in trans or in cis often yields divergent signaling events. In this review, we will revisit recent progress and discoveries of Thy-1–integrin interactions in trans and in cis, highlight their pathophysiological consequences and explore other potential binding partners of Thy-1 within the integrin regulation/signaling paradigm.
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Affiliation(s)
- Ping Hu
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, VA, United States
| | - Lisette Leyton
- Cellular Communication Laboratory, Program of Cellular and Molecular Biology, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile and Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - James S. Hagood
- Department of Pediatrics, Division of Pulmonology, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
- Program for Rare and Interstitial Lung Disease, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Thomas H. Barker
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, VA, United States
- *Correspondence: Thomas H. Barker,
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Hwang J, Park E, Choi YW, Min S, Oh ES. Emerging role of syndecans in maintaining homeostasis of colon epithelium during inflammation. Am J Physiol Cell Physiol 2022; 322:C960-C966. [PMID: 35385327 DOI: 10.1152/ajpcell.00048.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The syndecans are a family of transmembrane proteoglycans that are widespread in mammalian tissues. Located at the cell surface membrane, they contribute to modulating the composition of the extracellular matrix via glycosaminoglycan chains (GAGs) attached to their extracellular domains. Syndecans can interact with a variety of extracellular ligands through their core proteins and GAGs, and may also transmit signals through their transmembrane domain to regulate intracellular functions. These properties enable syndecan to modulate glycocalyx formation, epithelial cell-to-cell connections for cell barrier formation, and epithelial cell-lamina propria interactions in the colon epithelium, all of which are crucial for the homeostasis of this tissue. Inflammation induces structural alterations of the colon epithelium, and accumulating evidence suggests that syndecan expression might play important regulatory functions during inflammation. This review summarizes the possible roles of syndecans in maintaining tissue homeostasis in the colon epithelium, especially under inflammation.
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Affiliation(s)
- Jisun Hwang
- Department of Life Sciences, Ewha Womans University, Seoul, Korea (South), Republic of
| | - Eunhye Park
- Department of Life Sciences, Ewha Womans University, Seoul, Korea (South), Republic of
| | - Yeong-Woo Choi
- Department of Life Sciences, Ewha Womans University, Seoul, Korea (South), Republic of
| | - Shinhye Min
- Department of Life Sciences, Ewha Womans University, Seoul, Korea (South), Republic of
| | - Eok-Soo Oh
- Department of Life Sciences, Ewha Womans University, Seoul, Korea (South), Republic of
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Salvianolic Acid B Suppresses ER Stress-Induced NLRP3 Inflammasome and Pyroptosis via the AMPK/FoxO4 and Syndecan-4/Rac1 Signaling Pathways in Human Endothelial Progenitor Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8332825. [PMID: 35340217 PMCID: PMC8947883 DOI: 10.1155/2022/8332825] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 02/18/2022] [Indexed: 12/18/2022]
Abstract
Mounting evidence demonstrates uncontrolled endoplasmic reticulum (ER) stress responses can activate the inflammasome, which generally results in endothelial dysfunction, a major pathogenetic factor of chronic inflammatory diseases such as atherosclerosis. Salvianolic acid B (SalB), produced by Radix Salviae, exerts antioxidative and anti-inflammatory activities in multiple cell types. However, SalB's effects on ER stress-related inflammasome and endothelial dysfunction remain unknown. Here, we showed SalB substantially abrogated ER stress-induced cell death and reduction in capillary tube formation, with declined intracellular reactive oxygen species (ROS) amounts and restored mitochondrial membrane potential (MMP), as well as increased expression of HO-1 and SOD2 in bone marrow-derived endothelial progenitor cells (BM-EPCs). ER stress suppression by CHOP or caspase-4 siRNA transfection attenuated the protective effect of SalB. Additionally, SalB alleviated ER stress-mediated pyroptotic cell death via the suppression of TXNIP/NLRP3 inflammasome, as evidenced by reduced cleavage of caspase-1 and interleukin- (IL-) 1β and IL-18 secretion levels. Furthermore, this study provided a mechanistic basis that AMPK/FoxO4/KLF2 and Syndecan-4/Rac1/ATF2 signaling pathway modulation by SalB substantially prevented BM-EPCs damage associated with ER stress by decreasing intracellular ROS amounts and inducing NLRP3-dependent pyroptosis. In summary, our findings identify that ER stress triggered mitochondrial ROS release and NLRP3 generation in BM-EPCs, while SalB inhibits NLRP3 inflammasome-mediated pyroptotic cell death by regulating the AMPK/FoxO4/KLF2 and Syndecan-4/Rac1/ATF2 pathways. The current findings reveal SalB as a potential new candidate for the treatment of atherosclerotic heart disease.
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Bandzerewicz A, Gadomska-Gajadhur A. Into the Tissues: Extracellular Matrix and Its Artificial Substitutes: Cell Signalling Mechanisms. Cells 2022; 11:914. [PMID: 35269536 PMCID: PMC8909573 DOI: 10.3390/cells11050914] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/02/2022] [Accepted: 03/04/2022] [Indexed: 02/06/2023] Open
Abstract
The existence of orderly structures, such as tissues and organs is made possible by cell adhesion, i.e., the process by which cells attach to neighbouring cells and a supporting substance in the form of the extracellular matrix. The extracellular matrix is a three-dimensional structure composed of collagens, elastin, and various proteoglycans and glycoproteins. It is a storehouse for multiple signalling factors. Cells are informed of their correct connection to the matrix via receptors. Tissue disruption often prevents the natural reconstitution of the matrix. The use of appropriate implants is then required. This review is a compilation of crucial information on the structural and functional features of the extracellular matrix and the complex mechanisms of cell-cell connectivity. The possibilities of regenerating damaged tissues using an artificial matrix substitute are described, detailing the host response to the implant. An important issue is the surface properties of such an implant and the possibilities of their modification.
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Guan Z, Sun Y, Mu L, Jiang Y, Fan J. Tenascin-C promotes bladder cancer progression and its action depends on syndecan-4 and involves NF-κB signaling activation. BMC Cancer 2022; 22:240. [PMID: 35246056 PMCID: PMC8896393 DOI: 10.1186/s12885-022-09285-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/09/2022] [Indexed: 02/07/2023] Open
Abstract
Background Bladder Cancer (BCa) is a severe genitourinary tract disease with an uncertain pathology. Increasing evidence indicates that the tumor microenvironment plays a decisive role with respect to cancer progression, and that this is driven by tumor cell interactions with stromal components. Tenascin-C (TN-C) is an important extracellular matrix (ECM) component, which has been reported to be involved in other types of cancer, such as breast cancer. The expression of TN-C in BCa tissue has been reported to be positively associated with the BCa pathological grade, yet the presence of urine TN-C is considered as an independent risk factor for BCa. However, the role of TN-C in BCa progression is still unknow. Thus, the object of the present investigation is to determine the role of TN-C in BCa progression and the involved mechanism. Methods In this study, expression of TN-C in BCa tissue of Chinese local people was determined by IHC. Patients corresponding to tumor specimens were flowed up by telephone call to get their prognostic data and analyzed by using SPSS 19.0 statistic package. In vitro mechanistic investigation was demonstrated by QT-qPCR, Western Blot, Plasmid transfection to establishment of high/low TN-C-expression stable cell line, Boyden Chamber Assay, BrdU incorporation, Wound Healing, laser scanning confocal microscopy (LSCM) and ELISA. Results TN-C expression in BCa tissue increases with tumor grade and is an independent risk factor for BCa patient. The in vitro investigation suggested that TN-C enhances BCa cell migration, invasion, proliferation and contributes to the elevated expression of EMT-related markers by activating NF-κB signaling, the mechanism of which involving in syndecan-4. Conclusions Expression of TN-C in BCa tissues of Chinese local people is increased according to tumor grade and is an independent risk factor. TN-C mediates BCa cell malignant behavior via syndecan-4 and NF-κB signaling. Although the mechanisms through which syndecan-4 is associated with the activation of NF-κB signaling are unclear, the data presented herein provide a foundation for future investigations into the role of TN-C in BCa progression. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09285-x.
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Affiliation(s)
- Zhenfeng Guan
- Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China.,Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, People's Republic of China
| | - Yi Sun
- Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Liang Mu
- Department of B ultrasound, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Yazhuo Jiang
- Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Jinhai Fan
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, People's Republic of China.
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Szabo K, Varga D, Vegh AG, Liu N, Xiao X, Xu L, Dux L, Erdelyi M, Rovo L, Keller-Pinter A. Syndecan-4 affects myogenesis via Rac1-mediated actin remodeling and exhibits copy-number amplification and increased expression in human rhabdomyosarcoma tumors. Cell Mol Life Sci 2022; 79:122. [PMID: 35128576 PMCID: PMC8818642 DOI: 10.1007/s00018-021-04121-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 12/14/2021] [Accepted: 12/29/2021] [Indexed: 12/18/2022]
Abstract
Skeletal muscle demonstrates a high degree of regenerative capacity repeating the embryonic myogenic program under strict control. Rhabdomyosarcoma is the most common sarcoma in childhood and is characterized by impaired muscle differentiation. In this study, we observed that silencing the expression of syndecan-4, the ubiquitously expressed transmembrane heparan sulfate proteoglycan, significantly enhanced myoblast differentiation, and fusion. During muscle differentiation, the gradually decreasing expression of syndecan-4 allows the activation of Rac1, thereby mediating myoblast fusion. Single-molecule localized superresolution direct stochastic optical reconstruction microscopy (dSTORM) imaging revealed nanoscale changes in actin cytoskeletal architecture, and atomic force microscopy showed reduced elasticity of syndecan-4-knockdown cells during fusion. Syndecan-4 copy-number amplification was observed in 28% of human fusion-negative rhabdomyosarcoma tumors and was accompanied by increased syndecan-4 expression based on RNA sequencing data. Our study suggests that syndecan-4 can serve as a tumor driver gene in promoting rabdomyosarcoma tumor development. Our results contribute to the understanding of the role of syndecan-4 in skeletal muscle development, regeneration, and tumorigenesis.
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Ballermann BJ, Nyström J, Haraldsson B. The Glomerular Endothelium Restricts Albumin Filtration. Front Med (Lausanne) 2021; 8:766689. [PMID: 34912827 PMCID: PMC8667033 DOI: 10.3389/fmed.2021.766689] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/05/2021] [Indexed: 12/29/2022] Open
Abstract
Inflammatory activation and/or dysfunction of the glomerular endothelium triggers proteinuria in many systemic and localized vascular disorders. Among them are the thrombotic microangiopathies, many forms of glomerulonephritis, and acute inflammatory episodes like sepsis and COVID-19 illness. Another example is the chronic endothelial dysfunction that develops in cardiovascular disease and in metabolic disorders like diabetes. While the glomerular endothelium is a porous sieve that filters prodigious amounts of water and small solutes, it also bars the bulk of albumin and large plasma proteins from passing into the glomerular filtrate. This endothelial barrier function is ascribed predominantly to the endothelial glycocalyx with its endothelial surface layer, that together form a relatively thick, mucinous coat composed of glycosaminoglycans, proteoglycans, glycolipids, sialomucins and other glycoproteins, as well as secreted and circulating proteins. The glycocalyx/endothelial surface layer not only covers the glomerular endothelium; it extends into the endothelial fenestrae. Some glycocalyx components span or are attached to the apical endothelial cell plasma membrane and form the formal glycocalyx. Other components, including small proteoglycans and circulating proteins like albumin and orosomucoid, form the endothelial surface layer and are bound to the glycocalyx due to weak intermolecular interactions. Indeed, bound plasma albumin is a major constituent of the endothelial surface layer and contributes to its barrier function. A role for glomerular endothelial cells in the barrier of the glomerular capillary wall to protein filtration has been demonstrated by many elegant studies. However, it can only be fully understood in the context of other components, including the glomerular basement membrane, the podocytes and reabsorption of proteins by tubule epithelial cells. Discovery of the precise mechanisms that lead to glycocalyx/endothelial surface layer disruption within glomerular capillaries will hopefully lead to pharmacological interventions that specifically target this important structure.
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Affiliation(s)
| | - Jenny Nyström
- Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Börje Haraldsson
- Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
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Hu J, Li Y, Wei Z, Chen H, Sun X, Zhou Q, Zhang Q, Yin Y, Guo M, Chen J, Zhai G, Xu B, Xie J. A reduction in the vascular smooth muscle cell focal adhesion component syndecan-4 is associated with abdominal aortic aneurysm formation. Clin Transl Med 2021; 11:e605. [PMID: 34936241 PMCID: PMC8693440 DOI: 10.1002/ctm2.605] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 09/18/2021] [Accepted: 09/23/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Abdominal aortic aneurysm (AAA) is a serious vascular disease for which there is no effective drug treatment. The incidence of AAA increases significantly as a subject ages, and the molecular mechanism of AAA formation remains elusive. In the present study, we investigated the role of syndecan-4 (SDC4), an important component of focal adhesions, in AAA formation and its association with phenotypic changes in vascular smooth muscle cells (VSMCs). METHODS AND RESULTS The protein expression levels of SDC4 were significantly decreased in human AAA tissue and those of an AAA mouse model. Moreover, SDC4 knockout (KO) in mice accelerated the formation and rupture of AAAs induced by angiotensin II (Ang II) and calcium chloride (CaCl2 ) Mechanistically, the decrease in SDC4 led to the transformation of cultured VSMCs from a contractile to a secretory phenotype. The RhoA-F/G-actin-myocardin-related transcription factor-A (MRTF-A) signalling pathway was shown to be involved in SDC4-dependent VSMC alteration. Sphingosine-1-phosphate (S1P), a G-protein-coupled receptor, attenuated the AAA formation in SDC4-KO and wild-type (WT) mice in response to Ang II and CaCl2 stimulation. CONCLUSION We herein demonstrated that silencing SDC4 was associated with increased AAA formation and phenotypic changes in VSMCs via the RhoA-F/G-actin-MRTF-A pathway. These findings indicated that a reduction in SDC4 expression was an important pathological alteration and potential therapeutic target for AAA formation.
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Affiliation(s)
- Jiaxin Hu
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Yuyu Li
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Zhonghai Wei
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Haiting Chen
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Xuan Sun
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Qing Zhou
- Department of Cardiac Surgery, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjingChina
| | - Qi Zhang
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Yong Yin
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Meng Guo
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Jianzhou Chen
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Guangyao Zhai
- Department of Cardiology, Beijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Biao Xu
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
| | - Jun Xie
- Department of Cardiology, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Nanjing UniversityNanjingChina
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Rapraeger AC. Syndecans and Their Synstatins: Targeting an Organizer of Receptor Tyrosine Kinase Signaling at the Cell-Matrix Interface. Front Oncol 2021; 11:775349. [PMID: 34778093 PMCID: PMC8578902 DOI: 10.3389/fonc.2021.775349] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/27/2021] [Indexed: 01/11/2023] Open
Abstract
Receptor tyrosine kinases (RTKs) and integrin matrix receptors have well-established roles in tumor cell proliferation, invasion and survival, often functioning in a coordinated fashion at sites of cell-matrix adhesion. Central to this coordination are syndecans, another class of matrix receptor, that organize RTKs and integrins into functional units, relying on docking motifs in the syndecan extracellular domains to capture and localize RTKs (e.g., EGFR, IGF-1R, VEGFR2, HER2) and integrins (e.g., αvβ3, αvβ5, α4β1, α3β1, α6β4) to sites of adhesion. Peptide mimetics of the docking motifs in the syndecans, called “synstatins”, prevent assembly of these receptor complexes, block their signaling activities and are highly effective against tumor cell invasion and survival and angiogenesis. This review describes our current understanding of these four syndecan-coupled mechanisms and their inhibitory synstatins (SSTNIGF1R, SSTNVEGFR2, SSTNVLA-4, SSTNEGFR and SSTNHER2).
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Affiliation(s)
- Alan C Rapraeger
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
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Sadoughi F, Hallajzadeh J, Mirsafaei L, Asemi Z, Zahedi M, Mansournia MA, Yousefi B. Cardiac fibrosis and curcumin: a novel perspective on this natural medicine. Mol Biol Rep 2021; 48:7597-7608. [PMID: 34648140 DOI: 10.1007/s11033-021-06768-1] [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: 05/22/2021] [Accepted: 09/10/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND According to WHO statistics, cardiovascular disease are the leading causes of death in the world. One of the main factors which is causing heart failure, systolic and diastolic dysfunction, and arrythmias is a condition named cardiac fibrosis. This condition is defined by the accumulation of fibroblast-produced ECM in myocardium layer of the heart. OBJECTIVE Accordingly, the current review aims to depict the role of curcumin in the regulation of different signaling pathways that are involved in cardiac fibrosis. RESULTS A great number of cellular and molecular mechanisms such as oxidative stress, inflammation, and mechanical stress are acknowledged to be involved in cardiac fibrosis. Despite the available therapeutic procedures which are designed to target these mechanisms in order to prevent cardiac fibrosis, still, effective therapeutic methods are needed. Curcumin is a natural Chinese medicine which currently has been declared to have therapeutic properties such as anti-oxidant and immunomodulatory activities. In this review, we have gathered several experimental studies in order to represent diverse impacts of this turmeric derivative on pathogenic factors of cardiac fibrosis. CONCLUSION Curcumin might open new avenues in the field of cardiovascular treatment.
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Affiliation(s)
- Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Jamal Hallajzadeh
- Department of Biochemistry and Nutrition, Medicinal Plants Research Center, Maragheh University of Medical Sciences, Maragheh, Iran.
| | - Liaosadat Mirsafaei
- Department of Cardiology, Ramsar Campus, Mazandaran University of Medical Sciences, Sari, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Mahdi Zahedi
- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgān, Iran.
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors. Cancers (Basel) 2021; 13:cancers13205090. [PMID: 34680238 PMCID: PMC8534003 DOI: 10.3390/cancers13205090] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Major angiogenic growth factors activate downstream signaling cascades by interacting with both receptor tyrosine kinases (RTKs) and cell surface proteoglycans, such as heparan sulfate proteoglycans (HSPGs). As current anti-angiogenesis regimens in cancer are often faced with resistance, alternative therapeutic strategies are highly needed. The aim of our study was to investigate the impact on angiogenic signaling when we interfered with growth factor-HSPG interactions using a CXCL9 chemokine-derived peptide with high affinity for HS. Abstract Growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) are important angiogenesis-mediating factors. They exert their effects not only through their respective receptor tyrosine kinases (RTKs), but they also require molecular pairing with heparan sulfate proteoglycans (HSPGs). Angiogenic growth factors and their signaling pathways are commonly targeted in current anti-angiogenic cancer therapies but have unfortunately insufficient impact on patient survival. Considering their obvious role in pathological angiogenesis, HS-targeting drugs have become an appealing new strategy. Therefore, we aimed to reduce angiogenesis through interference with growth factor-HS binding and downstream signaling using a CXCL9-derived peptide with a high affinity for glycosaminoglycans (GAGs), CXCL9(74-103). We showed that CXCL9(74-103) reduced EGF-, VEGF165- and FGF-2-mediated angiogenic processes in vitro, such as endothelial cell proliferation, chemotaxis, adhesion and sprouting, without exerting cell toxicity. CXCL9(74-103) interfered with growth factor signaling in diverse ways, e.g., by diminishing VEGF165 binding to HS and by direct association with FGF-2. The dependency of CXCL9(74-103) on HS for binding to HMVECs and for exerting its anti-angiogenic activity was also demonstrated. In vivo, CXCL9(74-103) attenuated neovascularization in the Matrigel plug assay, the corneal cauterization assay and in MDA-MB-231 breast cancer xenografts. Additionally, CXCL9(74-103) reduced vascular leakage in the retina of diabetic rats. In contrast, CXCL9(86-103), a peptide with low GAG affinity, showed no overall anti-angiogenic activity. Altogether, our results indicate that CXCL9(74-103) reduces angiogenesis by interfering with multiple HS-dependent growth factor signaling pathways.
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Barua D, Nagel M, Winklbauer R. Cell-cell contact landscapes in Xenopus gastrula tissues. Proc Natl Acad Sci U S A 2021; 118:e2107953118. [PMID: 34544871 PMCID: PMC8488617 DOI: 10.1073/pnas.2107953118] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2021] [Indexed: 01/26/2023] Open
Abstract
Molecular and structural facets of cell-cell adhesion have been extensively studied in monolayered epithelia. Here, we perform a comprehensive analysis of cell-cell contacts in a series of multilayered tissues in the Xenopus gastrula model. We show that intercellular contact distances range from 10 to 1,000 nm. The contact width frequencies define tissue-specific contact spectra, and knockdown of adhesion factors modifies these spectra. This allows us to reconstruct the emergence of contact types from complex interactions of the factors. We find that the membrane proteoglycan Syndecan-4 plays a dominant role in all contacts, including narrow C-cadherin-mediated junctions. Glypican-4, hyaluronic acid, paraxial protocadherin, and fibronectin also control contact widths, and unexpectedly, C-cadherin functions in wide contacts. Using lanthanum staining, we identified three morphologically distinct forms of glycocalyx in contacts of the Xenopus gastrula, which are linked to the adhesion factors examined and mediate cell-cell attachment. Our study delineates a systematic approach to examine the varied contributions of adhesion factors individually or in combinations to nondiscrete and seemingly amorphous intercellular contacts.
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Affiliation(s)
- Debanjan Barua
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
| | - Martina Nagel
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
| | - Rudolf Winklbauer
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
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Maeso-Alonso L, López-Ferreras L, Marques MM, Marin MC. p73 as a Tissue Architect. Front Cell Dev Biol 2021; 9:716957. [PMID: 34368167 PMCID: PMC8343074 DOI: 10.3389/fcell.2021.716957] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
The TP73 gene belongs to the p53 family comprised by p53, p63, and p73. In response to physiological and pathological signals these transcription factors regulate multiple molecular pathways which merge in an ensemble of interconnected networks, in which the control of cell proliferation and cell death occupies a prominent position. However, the complex phenotype of the Trp73 deficient mice has revealed that the biological relevance of this gene does not exclusively rely on its growth suppression effects, but it is also intertwined with other fundamental roles governing different aspects of tissue physiology. p73 function is essential for the organization and homeostasis of different complex microenvironments, like the neurogenic niche, which supports the neural progenitor cells and the ependyma, the male and female reproductive organs, the respiratory epithelium or the vascular network. We propose that all these, apparently unrelated, developmental roles, have a common denominator: p73 function as a tissue architect. Tissue architecture is defined by the nature and the integrity of its cellular and extracellular compartments, and it is based on proper adhesive cell-cell and cell-extracellular matrix interactions as well as the establishment of cellular polarity. In this work, we will review the current understanding of p73 role as a neurogenic niche architect through the regulation of cell adhesion, cytoskeleton dynamics and Planar Cell Polarity, and give a general overview of TAp73 as a hub modulator of these functions, whose alteration could impinge in many of the Trp73 -/- phenotypes.
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Affiliation(s)
- Laura Maeso-Alonso
- Departamento de Biología Molecular, Instituto de Biomedicina (IBIOMED), University of León, León, Spain
| | - Lorena López-Ferreras
- Departamento de Biología Molecular, Instituto de Biomedicina (IBIOMED), University of León, León, Spain
| | - Margarita M Marques
- Departamento de Producción Animal, Instituto de Desarrollo Ganadero y Sanidad Animal, University of León, León, Spain
| | - Maria C Marin
- Departamento de Biología Molecular, Instituto de Biomedicina (IBIOMED), University of León, León, Spain
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Coutinho FP, Green CR, Acosta ML, Rupenthal ID. Xentry-Gap19 inhibits Connexin43 hemichannel opening especially during hypoxic injury. Drug Deliv Transl Res 2021; 10:751-765. [PMID: 32318976 PMCID: PMC7223318 DOI: 10.1007/s13346-020-00763-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hypoxic injury results in cell death, tissue damage and activation of inflammatory pathways. This is mediated by pathological Connexin43 (Cx43) hemichannel (HC) opening resulting in osmotic and ionic imbalances as well as cytokine production perpetuating the inflammatory environment. Gap19 is an intracellularly acting Cx43 mimetic peptide that blocks HC opening and thus promotes cell survival. However, native Gap19, which must enter the cell in order to function, exhibits low cell permeability. In this study, Gap19 was conjugated to the cell-penetrating peptide, Xentry, to investigate if cellular uptake could be improved while maintaining peptide function. Cellular uptake of Xentry-Gap19 (XG19) was much greater than that of native Gap19 even under normal cell culture conditions. Peptide function was maintained post uptake as shown by reduced ethidium homodimer influx and ATP release due to Cx43 HC block. While XG19 blocked pathologic HC opening though, normal gap junction communication required for cell repair and survival mechanisms was not affected as shown in a dye scrape-load assay. Under hypoxic conditions, increased expression of Syndecan-4, a plasma membrane proteoglycan targeted by Xentry, enabled even greater XG19 uptake leading to higher inhibition of ATP release and greater cell survival. This suggests that XG19, which is targeted specifically to hypoxic cells, can efficiently and safely block Cx43 HC and could therefore be a novel treatment for hypoxic and inflammatory diseases.
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