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      Differential Wound Healing Capacity of Mesenchymal Stem Cell-Derived Exosomes Originated From Bone Marrow, Adipose Tissue and Umbilical Cord Under Serum- and Xeno-Free Condition

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          Abstract

          Exosomes are nano-scale and closed membrane vesicles which are promising for therapeutic applications due to exosome-enclosed therapeutic molecules such as DNA, small RNAs, proteins and lipids. Recently, it has been demonstrated that mesenchymal stem cell (MSC)-derived exosomes have capacity to regulate many biological events associated with wound healing process, such as cell proliferation, cell migration and blood vessel formation. This study investigated the regenerative potentials for cutaneous tissue, in regard to growth factors associated with wound healing and skin cell proliferation and migration, by exosomes released from primary MSCs originated from bone marrow (BM), adipose tissue (AD), and umbilical cord (UC) under serum- and xeno-free condition. We found crucial wound healing-mediated growth factors, such as vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2), hepatocyte growth factor (HGF), and platelet-derived growth factor BB (PDGF-BB) in exosomes derived from all three MSC sources. However, expression levels of these growth factors in exosomes were influenced by MSC origins, especially transforming growth factor beta (TGF-β) was only detected in UCMSC-derived exosomes. All exosomes released by three MSCs sources induced keratinocyte and fibroblast proliferation and migration; and, the induction of cell migration is a dependent manner with the higher dose of exosomes was used (20 μg), the faster migration rate was observed. Additionally, the influences of exosomes on cell proliferation and migration was associated with exosome origins and also target cells of exosomes that the greatest induction of primary dermal fibroblasts belongs to BMMSC-derived exosomes and keratinocytes belongs to UCMSC-derived exosomes. Data from this study indicated that BMMSCs and UCMSCs under clinical condition secreted exosomes are promising to develop into therapeutic products for wound healing treatment.

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          Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts

          Xue-Li Hu, Juan Wang, Xin Zhou … (2016)
          Prolonged healing and scar formation are two major challenges in the treatment of soft tissue trauma. Adipose mesenchymal stem cells (ASCs) play an important role in tissue regeneration, and recent studies have suggested that exosomes secreted by stem cells may contribute to paracrine signaling. In this study, we investigated the roles of ASCs-derived exosomes (ASCs-Exos) in cutaneous wound healing. We found that ASCs-Exos could be taken up and internalized by fibroblasts to stimulate cell migration, proliferation and collagen synthesis in a dose-dependent manner, with increased genes expression of N-cadherin, cyclin-1, PCNA and collagen I, III. In vivo tracing experiments demonstrated that ASCs-Exos can be recruited to soft tissue wound area in a mouse skin incision model and significantly accelerated cutaneous wound healing. Histological analysis showed increased collagen I and III production by systemic administration of exosomes in the early stage of wound healing, while in the late stage, exosomes might inhibit collagen expression to reduce scar formation. Collectively, our findings indicate that ASCs-Exos can facilitate cutaneous wound healing via optimizing the characteristics of fibroblasts. Our results provide a new perspective and therapeutic strategy for the use of ASCs-Exos in soft tissue repair.
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            Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway.

            Bin Zhang, Xiaodan Wu, Xu Zhang … (2015)
            Human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms are still not well understood. In this study, we isolated and characterized the exosomes from hucMSCs (hucMSC-Ex) and demonstrated that hucMSC-Ex promoted the proliferation, migration, and tube formation of endothelial cells in a dose-dependent manner. Furthermore, we demonstrated that hucMSC-Ex promoted wound healing and angiogenesis in vivo by using a rat skin burn model. We discovered that hucMSC-Ex promoted β-catenin nuclear translocation and induced the increased expression of proliferating cell nuclear antigen, cyclin D3, N-cadherin, and β-catenin and the decreased expression of E-cadherin. The activation of Wnt/β-catenin is critical in the induction of angiogenesis by hucMSC-Ex, which could be reversed by β-catenin inhibitor ICG-001. Wnt4 was delivered by hucMSC-Ex, and the knockdown of Wnt4 in hucMSC-Ex abrogated β-catenin nuclear translocation in endothelial cells. The in vivo proangiogenic effects were also inhibited by interference of Wnt4 expression in hucMSC-Ex. Taken together, these results suggest that hucMSC-Ex-mediated Wnt4 induces β-catenin activation in endothelial cells and exerts proangiogenic effects, which could be an important mechanism for cutaneous wound healing.
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              Fibroblast Growth Factors: Biology, Function, and Application for Tissue Regeneration

              Ye-Rang Yun, Jong-Eun Won, Eunyi Jeon … (2010)
              Fibroblast growth factors (FGFs) that signal through FGF receptors (FGFRs) regulate a broad spectrum of biological functions, including cellular proliferation, survival, migration, and differentiation. The FGF signal pathways are the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway, among which the RAS/MAP kinase pathway is known to be predominant. Several studies have recently implicated the in vitro biological functions of FGFs for tissue regeneration. However, to obtain optimal outcomes in vivo, it is important to enhance the half-life of FGFs and their biological stability. Future applications of FGFs are expected when the biological functions of FGFs are potentiated through the appropriate use of delivery systems and scaffolds. This review will introduce the biology and cellular functions of FGFs and deal with the biomaterials based delivery systems and their current applications for the regeneration of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve tissues.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Mol Biosci
                Journal ID (iso-abbrev): Front Mol Biosci
                Journal ID (publisher-id): Front. Mol. Biosci.
                Title: Frontiers in Molecular Biosciences
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 2296-889X
                Publication date (Electronic): 24 June 2020
                Publication date Collection: 2020
                Volume: 7
                Electronic Location Identifier: 119
                Affiliations
                [1] 1Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Health Care System , Hanoi, Vietnam
                [2] 2Vinmec Hightech Center, Vinmec Healthcare System , Hanoi, Vietnam
                [3] 3College of Health Sciences, Vin University , Hanoi, Vietnam
                [4] 4University of Science, Viet Nam University , Hanoi, Vietnam
                Author notes

                Edited by: Marco Falasca, Curtin University, Australia

                Reviewed by: Letizia De Chiara, University of Florence, Italy; Veronika Butin-Israeli, Northwestern University, United States

                *Correspondence: Uyen Thi Trang Than v.uyenttt@ 123456vinmec.com ; uyentpp@ 123456yahoo.com

                This article was submitted to Molecular Diagnostics and Therapeutics, a section of the journal Frontiers in Molecular Biosciences

                †These authors have contributed equally to this work

                Article
                DOI: 10.3389/fmolb.2020.00119
                PMC ID: 7327117
                PubMed ID: 32671095
                SO-VID: 7425efc8-f8d8-4b68-8e03-bec639c52131
                Copyright © Copyright © 2020 Hoang, Nguyen, Nguyen, Nguyen, Do, Dang, Dam, Bui, Trinh, Vu, Hoang, Thanh and Than.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 11 March 2020
                Date accepted : 22 May 2020
                Page count
                Figures: 6, Tables: 2, Equations: 0, References: 61, Pages: 13, Words: 8894
                Categories
                Subject: Molecular Biosciences
                Subject: Original Research

                Keywords: exosomes,mesenchymal stem cells,bmmsc-derived exosomes,admsc-derived exosomes,ucmsc-derived exosomes,growth factors,wound healing
                Data availability:
                Keywords: exosomes, mesenchymal stem cells, bmmsc-derived exosomes, admsc-derived exosomes, ucmsc-derived exosomes, growth factors, wound healing

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