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      Stem Cell‐Derived Extracellular Vesicles as a Novel Potential Therapeutic Tool for Tissue Repair

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          Summary

          Stem cells, with their therapeutic potential in tissue repair and regeneration, have been widely used in translational medicine. Recent evidence suggests that the beneficial effects are mediated largely by their paracrine actions rather than the engraftment and differentiation at the injured sites. Extracellular vesicles (EVs), actively released from cells, play important roles in cell‐to‐cell communication and display multiple functions in tissue regeneration. In the present report, we will briefly review the current knowledge related to the therapeutic potential of EVs, particularly stem cell or progenitor cell‐derived ones for promoting tissue repair and regeneration, and focus on the restorative properties of exosomes/microvesicles in cutaneous wound healing, bone regeneration, hindlimb ischemia, and vascular injury repair. S tem C ells T ranslational M edicine 2017;6:1753–1758

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          Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis

          Jieyuan Zhang, Junjie Guan, Xin Niu … (2015)
          Background Human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) have emerged as a promising alternative for stem cell transplantation therapy. Exosomes derived from mesenchymal stem cells (MSC-Exos) can play important roles in repairing injured tissues. However, to date, no reports have demonstrated the use of hiPSC-MSC-Exos in cutaneous wound healing, and little is known regarding their underlying mechanisms in tissue repair. Methods hiPSC-MSC-Exos were injected subcutaneously around wound sites in a rat model and the efficacy of hiPSC-MSC-Exos was assessed by measuring wound closure areas, by histological and immunofluorescence examinations. We also evaluated the in vitro effects of hiPSC-MSC-Exos on both the proliferation and migration of human dermal fibroblasts and human umbilical vein endothelial cells (HUVECs) by cell-counting and scratch assays, respectively. The effects of exosomes on fibroblast collagen and elastin secretion were studied in enzyme-linked immunosorbent assays and quantitative reverse-transcriptase–polymerase chain reaction (qRT-PCR). In vitro capillary network formation was determined in tube-formation assays. Results Transplanting hiPSC-MSC-Exos to wound sites resulted in accelerated re-epithelialization, reduced scar widths, and the promotion of collagen maturity. Moreover, hiPSC-MSC-Exos not only promoted the generation of newly formed vessels, but also accelerated their maturation in wound sites. We found that hiPSC-MSC-Exos stimulated the proliferation and migration of human dermal fibroblasts and HUVECs in a dose-dependent manner in vitro. Similarly, Type I, III collagen and elastin secretion and mRNA expression by fibroblasts and tube formation by HUVECs were also increased with increasing hiPSC-MSC-Exos concentrations. Conclusions Our findings suggest that hiPSC-MSC-Exos can facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. These data provide the first evidence for the potential of hiPSC-MSC-Exos in treating cutaneous wounds.
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            Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.

            Johnathon Anderson, Henrik Johansson, Calvin S Graham … (2016)
            Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.
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              Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-β/SMAD2 Pathway During Wound Healing.

              Shuo Fang, Chen Xu, Yuntong Zhang … (2016)
              : Excessive scar formation caused by myofibroblast aggregations is of great clinical importance during skin wound healing. Studies have shown that mesenchymal stem cells (MSCs) can promote skin regeneration, but whether MSCs contribute to scar formation remains undefined. We found that umbilical cord-derived MSCs (uMSCs) reduced scar formation and myofibroblast accumulation in a skin-defect mouse model. We found that these functions were mainly dependent on uMSC-derived exosomes (uMSC-Exos) and especially exosomal microRNAs. Through high-throughput RNA sequencing and functional analysis, we demonstrated that a group of uMSC-Exos enriched in specific microRNAs (miR-21, -23a, -125b, and -145) played key roles in suppressing myofibroblast formation by inhibiting the transforming growth factor-β2/SMAD2 pathway. Finally, using the strategy we established to block miRNAs inside the exosomes, we showed that these specific exosomal miRNAs were essential for the myofibroblast-suppressing and anti-scarring functions of uMSCs both in vitro and in vivo. Our study revealed a novel role of exosomal miRNAs in uMSC-mediated therapy, suggesting that the clinical application of uMSC-derived exosomes might represent a strategy to prevent scar formation during wound healing.
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                Author and article information

                Contributors
                Yang Wang:
                ORCID: http://orcid.org/0000-0002-6649-5291
                wangyang63@126.com
                Journal
                Journal ID (nlm-ta): Stem Cells Transl Med
                Journal ID (iso-abbrev): Stem Cells Transl Med
                Journal ID (doi): 10.1002/(ISSN)2157-6580
                Journal ID (publisher-id): SCT3
                Title: Stem Cells Translational Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 2157-6564
                ISSN (Electronic): 2157-6580
                Publication date (Electronic): 27 June 2017
                Publication date Collection: September 2017
                Volume: 6
                Issue: 9 ( doiID: 10.1002/sct3.2017.6.issue-9 )
                Pages: 1753-1758
                Affiliations
                [ 1 ] Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital 600 Yishan Road Shanghai 200233 People's Republic of China
                [ 2 ] Department of Orthopedic Surgery Shanghai Jiao Tong University Affiliated Sixth People's Hospital 600 Yishan Road Shanghai 200233 People's Republic of China
                Author notes
                [*] [* ]Correspondence: Yang Wang, Ph.D., Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Telephone: 86‐21‐24056319; e‐mail: wangyang63@ 123456126.com
                Author information
                http://orcid.org/0000-0002-6649-5291
                Article
                Publisher ID: SCT312172
                DOI: 10.1002/sctm.16-0477
                PMC ID: 5689748
                PubMed ID: 28653443
                SO-VID: 29b6458e-4a52-4110-b892-6f136d08dce9
                Copyright © © 2017 The Authors S tem C ells T ranslational M edicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 29 November 2016
                Date accepted : 21 April 2017
                Page count
                Figures: 2, Tables: 3, Pages: 7, Words: 5223
                Categories
                Subject: Perspectives
                Subject: Bone Marrow Stem Cells
                Subject: Cord / Cord Blood Stem Cells (WJ‐MSCs)
                Subject: Induced Pluripotent stem cells
                Subject: Mesenchymal Stem Cells
                Subject: Angiogenesis
                Subject: Osteogenesis
                Subject: Wound Healing / Fibrosis
                Subject: Vascular Disease
                Subject: Perspectives
                Subject: Perspectives
                Custom metadata
                source-schema-version-number 2.0
                component-id sct312172
                cover-date September 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.4.1 mode:remove_FC converted:09.11.2017

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