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      Exosomes Derived from Bone Mesenchymal Stem Cells with the Stimulation of Fe 3O 4 Nanoparticles and Static Magnetic Field Enhance Wound Healing Through Upregulated miR-21-5p

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          Abstract

          Background

          Both magnetic nanoparticles (MNPs) and exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been reported to improve wound healing. In this study, novel exosomes (mag-BMSC-Exos) would be fabricated from BMSCs with the stimulation of MNPs and a static magnetic field (SMF) to further enhance wound repair.

          Methods

          Mag-BMSC-Exos, namely, exosomes derived from BMSCs preconditioned with Fe 3O 4 nanoparticles and a SMF, together with BMSC-Exos were both first isolated by ultracentrifugation, respectively. Afterwards, we conducted in vitro experiments, including scratch wound assays, transwell assays, and tube formation assays, and established an in vivo wound healing model. The miRNA expression profiles were compared between BMSC-Exos and mag-BMSC-Exos to detect the potential mechanism of improving wound healing. At last, the function of exosomal miR-21-5p during wound healing was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro.

          Results

          The optimal working magnetic condition was 50 µg/mL Fe 3O 4 nanoparticles combined with 100 mT SMF. In vitro, mag-BMSC-Exo administration promoted proliferation, migration and angiogenesis to a greater extent than BMSC-Exo administration. Local transplantation of mag-BMSC-Exos into rat skin wounds resulted in accelerated wound closure, narrower scar widths and enhanced angiogenesis compared with BMSC-Exo transplantation. Notably, miR-21-5p was found to be highly enriched in mag-BMSC-Exos and served as a critical mediator in mag-BMSC-Exo-induced regulatory effects through inhibition of SPRY2 and activation of the PI3K/AKT and ERK1/2 signaling pathways.

          Conclusion

          Mag-BMSC-Exos can further enhance wound healing than BMSC-Exos by improving angiogenesis and fibroblast function, and miR-21-5p upregulation in mag-BMSC-Exos might be the potential mechanism. This work offers an effective and promising protocol to improve wound healing in clinic.

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          Most cited references 38

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          Biological properties of extracellular vesicles and their physiological functions

          In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
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            Wound healing: an overview of acute, fibrotic and delayed healing.

            Acute wounds normally heal in a very orderly and efficient manner characterized by four distinct, but overlapping phases: hemostasis, inflammation, proliferation and remodeling. Specific biological markers characterize healing of acute wounds. Likewise, unique biologic markers also characterize pathologic responses resulting in fibrosis and chronic non-healing ulcers. This review describes the major biological processes associated with both normal and pathologic healing. The normal healing response begins the moment the tissue is injured. As the blood components spill into the site of injury, the platelets come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers the platelets to release clotting factors as well as essential growth factors and cytokines such as platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta). Following hemostasis, the neutrophils then enter the wound site and begin the critical task of phagocytosis to remove foreign materials, bacteria and damaged tissue. As part of this inflammatory phase, the macrophages appear and continue the process of phagocytosis as well as releasing more PDGF and TGF beta. Once the wound site is cleaned out, fibroblasts migrate in to begin the proliferative phase and deposit new extracellular matrix. The new collagen matrix then becomes cross-linked and organized during the final remodeling phase. In order for this efficient and highly controlled repair process to take place, there are numerous cell-signaling events that are required. In pathologic conditions such as non-healing pressure ulcers, this efficient and orderly process is lost and the ulcers are locked into a state of chronic inflammation characterized by abundant neutrophil infiltration with associated reactive oxygen species and destructive enzymes. Healing proceeds only after the inflammation is controlled. On the opposite end of the spectrum, fibrosis is characterized by excessive matrix deposition and reduced remodeling. Often fibrotic lesions are associated with increased densities of mast cells. By understanding the functional relationships of these biological processes of normal compared to abnormal wound healing, hopefully new strategies can be designed to treat the pathological conditions.
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              Extracellular vesicles: biology and emerging therapeutic opportunities.

              Within the past decade, extracellular vesicles have emerged as important mediators of intercellular communication, being involved in the transmission of biological signals between cells in both prokaryotes and higher eukaryotes to regulate a diverse range of biological processes. In addition, pathophysiological roles for extracellular vesicles are beginning to be recognized in diseases including cancer, infectious diseases and neurodegenerative disorders, highlighting potential novel targets for therapeutic intervention. Moreover, both unmodified and engineered extracellular vesicles are likely to have applications in macromolecular drug delivery. Here, we review recent progress in understanding extracellular vesicle biology and the role of extracellular vesicles in disease, discuss emerging therapeutic opportunities and consider the associated challenges.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                ijn
                intjnano
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                19 October 2020
                2020
                : 15
                : 7979-7993
                Affiliations
                [1 ]Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100730, People’s Republic of China
                [2 ]Medical Science Research Center (MRC), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100730, People’s Republic of China
                [3 ]Umibio (Shanghai) Co. Ltd , Shanghai 201210, People’s Republic of China
                [4 ]Beijing Key Laboratory for Genetic Research of Bone and Joint Disease , Beijing 100730, People’s Republic of China
                Author notes
                Correspondence: Hai Wang Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , No. 1 Shuaifuyuan, Beijing100730, People’s Republic of China Email wanghai907@hotmail.com
                Zhihong Wu Medical Science Research Center (MRC), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , No. 1 Shuaifuyuan, Beijing100730, People’s Republic of China Email wuzh3000@126.com
                Article
                275650
                10.2147/IJN.S275650
                7585514
                33116513
                © 2020 Wu et al.

                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).

                Page count
                Figures: 6, References: 38, Pages: 15
                Funding
                Funded by: Beijing Municipal Natural Science Foundation, open-funder-registry 10.13039/501100004826;
                Award ID: 7202167
                Funded by: Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program;
                Award ID: 2019ZLH209
                Funded by: Science Foundation for Young Scholars of Peking Union Medical College Hospital;
                Award ID: pumch201912146
                Funded by: Fundamental Research Funds for Central Public Welfare Research Institutes, Chinese Academy of Medical Sciences;
                Award ID: 2016ZX310177-7
                This work was supported by Beijing Municipal Natural Science Foundation (7202167); Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program (2019ZLH209); Science Foundation for Young Scholars of Peking Union Medical College Hospital (No. pumch201912146); Fundamental Research Funds for Central Public Welfare Research Institutes, Chinese Academy of Medical Sciences (2016ZX310177-7).
                Categories
                Original Research

                Molecular medicine

                exosomes, wound healing, mir-21-5p, angiogenesis, fibroblast function

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