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      Human Adipose-Derived Mesenchymal Stem Cells-Derived Exosomal microRNA-19b Promotes the Healing of Skin Wounds Through Modulation of the CCL1/TGF-β Signaling Axis

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          Abstract

          Introduction

          Human adipose-derived mesenchymal stem cells (ADMSCs) with their secretory factors are able to induce collagen synthesis and fibroblast migration in the wound healing process. This study is launched to figure out the effect of human ADMSCs-derived exosomes on skin wound healing.

          Methods

          ADMSCs were extracted and ADMSCs-derived exosomes were identified. Skin damage models were established by treating HaCaT cells and human skin fibroblasts with H 2O 2. Next, the roles of ADMSCs and their derived exosomes were investigated. The exosomal miRNA then was analyzed, and the function of miRNA on the H 2O 2-induced cells was studied by miRNA suppression. Bioinformatics analysis, luciferase activity and RIP assays were implemented to find the target genes ofthe miRNA and the modulated pathways. A mouse skin damage model was induced to elucidate the effects of exosomes in vivo by injecting exosomes.

          Results

          H 2O 2 treatment significantly reduced the viability of HaCaT cells and increased their apoptosis rate. Co-culture with ADMSCs or their derived exosomes could improve the cell damage caused by H 2O 2. Meanwhile, H 2O 2 treatment promoted the internalization of exosomes. ADMSCs and their derived exosomes significantly increased miR-19b expression in the recipient cells, while inhibiting miR-19b resulted in a reduction in the therapeutic effect of ADMSCs-derived exosomes. Besides, miR-19b regulated the TGF-β pathway by targeting CCL1. The therapeutic effect of exosomes was further confirmed by a mouse model of skin damage.

          Conclusion

          Our study indicates that exosomal miR-19b derived from ADMSCs regulates the TGF-β pathway by targeting CCL1, thereby promoting the healing of skin wounds.

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          Most cited references43

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          Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis

          Byong Seung Cho, Jin Kim, Dae Ha … (2018)
          Exosomes are nano-sized vesicles (30–200 nm) constantly released by almost all cells. The ability of exosomes to travel between cells and deliver their cargo, which includes lipids, proteins, and nucleic acids, makes them an appealing cell-free therapy option to treat multiple diseases. Here, we investigated for the first time whether human adipose tissue-derived mesenchymal stem cell-derived exosomes (ASC-exosomes) can ameliorate atopic dermatitis (AD) in an in vivo mouse model. When injected either intravenously (IV) or subcutaneously (SC) into NC/Nga mice treated with house dust mite antigens, ASC-exosomes were found to reduce pathological symptoms such as clinical score, the levels of serum IgE, the number of eosinophils in blood, and the infiltration of mast cells, CD86+, and CD206+ cells in skin lesions. ASC-exosomes also significantly reduced mRNA expression of various inflammatory cytokines such as interleukin (IL)-4, IL-23, IL-31, and tumor necrosis factor-α (TNF-α) in AD skin lesions of Nc/Nga mice. Taken together, these results suggest that ASC-exosomes can be a novel promising cell-free therapeutic modality for AD treatment. Electronic supplementary material The online version of this article (10.1186/s13287-018-0939-5) contains supplementary material, which is available to authorized users.
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            Adipose mesenchymal stem cell‐derived exosomes promote cell proliferation, migration, and inhibit cell apoptosis via Wnt/β‐catenin signaling in cutaneous wound healing

            Tao Ma, Bingchuan Fu, Xin Yang … (2018)
            Cutaneous wounds, a type of soft tissue injury, are difficult to heal in aging. Differentiation, migration, proliferation, and apoptosis of skin cells are identified as key factors during wound healing processes. Mesenchymal stem cells have been documented as possible candidates for wound healing treatment because their use could augment the regenerative capacity of many tissues. However, the effects of exosomes derived from adipose-derived stem cell (ADSC-exos) on cutaneous wound healing remain to be carefully elucidated. In this present study, HaCaT cells were exposed to hydrogen peroxide (H2 O 2 ) for the establishment of the skin lesion model. Cell Counting Kit-8 assay, migration assay, and flow cytometry assay were conducted to detect the biological function of ADSC-exos in skin lesion model. Finally, the possible mechanism was further investigated using Western blot assay. The successful construction of the skin lesion model was confirmed by results of the enhanced cell apoptosis of HaCaT cells induced by H 2 O 2 , the increased Bax expression and decreased Bcl-2 expression. CD9 and CD63 expression evidenced the existence of ADSC-exos. The results of functional experiments demonstrated that ADSC-exos could prompt cell proliferation and migration of HaCaT cells, and repress cell apoptosis of HaCaT cells. In addition, the activation of Wnt/β-catenin signaling was confirmed by the enhanced expression of β-catenin at the protein level. Collectively, our findings suggest that ADSC-exos play a positive role in cutaneous wound healing possibly via Wnt/β-catenin signaling. Our study may provide new insights into the therapeutic target for cutaneous wound healing.
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              Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Stimulated by Deferoxamine Accelerate Cutaneous Wound Healing by Promoting Angiogenesis

              Jianing Ding, Xin. Wang, Bi Chen … (2019)
              The exosomes are derived from mesenchymal stem cells (MSCs) and may be potentially used as an alternative for cell therapy, for treating diabetic wounds, and aid in angiogenesis. This study, aimed to investigate whether exosomes originated from bone marrow-derived MSCs (BMSCs) preconditioned by deferoxamine (DFO-Exos) exhibited superior proangiogenic property in wound repair and to explore the underlying mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were used for assays involving cell proliferation, scratch wound healing, and tube formation. To test the effects in vivo, streptozotocin-induced diabetic rats were established. Two weeks after the procedure, histological analysis was used to measure wound-healing effects, and the neovascularization was evaluated as well. Our findings demonstrated that DFO-Exos activate the PI3K/AKT signaling pathway via miR-126 mediated PTEN downregulation to stimulate angiogenesis in vitro. This contributed to enhanced wound healing and angiogenesis in streptozotocin-induced diabetic rats in vivo. Our results suggest that, in cell-free therapies, exosomes derived from DFO preconditioned stem cells manifest increased proangiogenic ability.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Clin Cosmet Investig Dermatol
                Journal ID (iso-abbrev): Clin Cosmet Investig Dermatol
                Journal ID (publisher-id): ccid
                Journal ID (pmc): ccid
                Title: Clinical, Cosmetic and Investigational Dermatology
                Publisher: Dove
                ISSN (Electronic): 1178-7015
                Publication date (Electronic): 15 December 2020
                Publication date Collection: 2020
                Volume: 13
                Pages: 957-971
                Affiliations
                [1 ]Department of Dermatology, The Third Affiliated Hospital of Zunyi Medical University (The First People’s Hospital of Zunyi) , Zunyi, Guizhou 563000, People’s Republic of China
                [2 ]Department of Pharmacy, The Third People’s Hospital of Zunyi , Zunyi, Guizhou 563000, People’s Republic of China
                [3 ]Department of Project, MDL Biotech. Co.Ltd , Beijing 100080, People’s Republic of China
                Author notes
                Correspondence: Hongyun Chen Email Chenhongyuan4242@163.com
                Article
                Publisher ID: 274370
                DOI: 10.2147/CCID.S274370
                PMC ID: 7751444
                PubMed ID: 33364805
                SO-VID: 4ba572ed-7f9a-4fd4-ae31-100df1b25dc6
                Copyright © © 2020 Cao et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 28 July 2020
                Date accepted : 12 November 2020
                Page count
                Figures: 8, References: 43, Pages: 15
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Dermatology
                Keywords: human adipose-derived mesenchymal stem cells,exosome,microrna-19b,healing of skin wounds,ccl1,tgf-β signaling pathway
                Data availability:
                ScienceOpen disciplines: Dermatology
                Keywords: human adipose-derived mesenchymal stem cells, exosome, microrna-19b, healing of skin wounds, ccl1, tgf-β signaling pathway

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