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      Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle‐Mediated Delivery of miRNA

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          Abstract

          Mesenchymal stem cells from corneal stromal stem cells (CSSC) prevent fibrotic scarring and stimulate regeneration of transparent stromal tissue after corneal wounding in mice. These effects rely on the ability of CSSC to block neutrophil infiltration into the damaged cornea. The current study investigated the hypothesis that tissue regeneration by CSSC is mediated by secreted extracellular vesicles (EVs). CSSC produced EVs 130–150 nm in diameter with surface proteins that include CD63, CD81, and CD9. EVs from CSSC reduced visual scarring in murine corneal wounds as effectively as did live cells, but EVs from human embryonic kidney (HEK)293T cells had no regenerative properties. CSSC EV treatment of wounds decreased expression of fibrotic genes Col3a1 and Acta2, blocked neutrophil infiltration, and restored normal tissue morphology. CSSC EVs labeled with carboxyfluorescein succinimidyl ester dye, rapidly fused with corneal epithelial and stromal cells in culture, transferring microRNA (miRNA) to the target cells. Knockdown of mRNA for Alix, a component of the endosomal sorting complex required for transport, using siRNA, resulted in an 85% reduction of miRNA in the secreted EVs. The EVs with reduced miRNA were ineffective at blocking corneal scarring. Furthermore, CSSC with reduced Alix expression also lost their regenerative function, suggesting EVs as an obligate component in the delivery of miRNA. The results of these studies support an essential role for extracellular vesicles in the process by which CSSC cells block scarring and initiate regeneration of transparent corneal tissue after wounding. EVs appear to serve as a delivery vehicle for miRNA, which affects the regenerative action. stem cells translational medicine 2019;8:1192–1201

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          Most cited references39

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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.

          : 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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            MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis

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              MSC-exosome: A novel cell-free therapy for cutaneous regeneration

              Cutaneous regeneration is a dynamic and complex process that requires a series of coordinated interactions involving epidermal cells, dermal cells, growth factors, the extracellular matrix (ECM), nerves and blood vessels at a damaged site. Mesenchymal stromal cells (MSCs) have been reported to participate in all afore-mentioned stages. Exosomes are one of the key secretory products of MSCs, resembling the effect of parental MSCs. They can shuttle various proteins, messenger RNA (mRNA) and microRNAs (miRNAs) to modulate the activity of recipient cells, and play important roles in cutaneous wound healing. Compared with MSCs, exosomes are more convenient to store and transport. Moreover, they avoid many risks associated with cell transplantation. Therefore, MSC-exosome-mediated therapy may be more safe and efficient. In this review, we summarize the latest studies and observations on the role of MSC-exosome in the acute and chronic wound model and provide a comprehensive understanding of the role of exosomes in wound healing. This review can assist investigators in exploring new therapeutic strategies for enhancing the efficacy of MSC-exosome for cutaneous repair and regeneration.
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                Author and article information

                Contributors
                jlfunder@pitt.edu
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                2157-6564
                2157-6580
                10 July 2019
                November 2019
                : 8
                : 11 ( doiID: 10.1002/sct3.v8.11 )
                : 1192-1201
                Affiliations
                [ 1 ] Department of Ophthalmology, University of Pittsburgh Pittsburgh Pennsylvania USA
                [ 2 ] Kantonsspital Winterthur Zurich Switzerland
                [ 3 ] Stein Eye Institute University of California Los Angeles Los Angeles California USA
                Author notes
                [*] [* ]Correspondence: James L. Funderburgh, Ph.D., Department of Ophthalmology, 203 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA. Telephone: 412‐647‐3853; e‐mail: jlfunder@ 123456pitt.edu
                Author information
                https://orcid.org/0000-0002-6192-6363
                Article
                SCT312537
                10.1002/sctm.18-0297
                6811691
                31290598
                c25e442c-a5a7-493b-af86-7e57ca7e000c
                © 2019 The Authors. stem cells translational medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ 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
                : 31 December 2018
                : 25 May 2019
                Page count
                Figures: 7, Tables: 0, Pages: 10, Words: 8531
                Funding
                Funded by: California Institute for Regenerative Medicine
                Award ID: CLIN1‐08686
                Funded by: NEI
                Award ID: R01 EY021797
                Award ID: R01 EY028557
                Funded by: Department of Defense
                Award ID: W81WH‐14‐1‐0465
                Funded by: Research to Prevent Blindness
                Funded by: Eye and Ear Foundation of Pittsburgh
                Funded by: NIH
                Award ID: P30 EY008098
                Award ID: EY016415
                Categories
                Enabling Technologies for Cell‐Based Clinical Translation
                Enabling Technologies for Cell‐Based Clinical Translation
                Custom metadata
                2.0
                sct312537
                November 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:24.10.2019

                mesenchymal stem cells,extracellular vesicles,exosomes,regeneration,cornea,microrna

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