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Human Adipose Mesenchymal Stem Cell-Derived Exosomes: A Key Player in Wound Healing

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Human adipose-derived mesenchymal stem cells (AMSCs) are an attractive resource for wound healing because their regenerative capacity improves injury repair. Recently, stem cell-derived exosomes have been shown to play a positive role in stem cell-based therapies. However, the effects of exosomes derived from AMSCs (AEXOs) on wound healing are unclear. In this study, we aimed to examine the role of AEXOs in attenuating inflammation and explore their effects in normal wound healing.

Methods:

We isolated exosomes from AMSCs and established a cellular model of inflammation by treatment with the inflammatory cytokines, interferon gamma and tumor necrosis factor alpha, to determine whether AEXOs can inhibit inflammation. We examined the wound healing effects of AEXOs in in vitro wound healing models and performed a miRNA array to understand the role of AEXOs in inflammation and wound healing.

Results:

A significant difference was observed in wound closure and the expression of anti-inflammatory and wound-healing-related factors between control and AEXO-treated cells.

Conclusion:

Our results showed that besides alleviating the inflammation response, AEXOs also promote wound healing. Thus, AEXOs represent a novel, stem-cell-based, therapeutic strategy for wound healing.

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References

  1. Rodriguez-Menocal L, Salgado M, Ford D, Van Badiavas E. Stimulation of skin and wound fibroblast migration by mesenchymal stem cells derived from normal donors and chronic wound patients. Stem Cells Transl Med. 2012;1:221–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhao P, Sui BD, Liu N, Lv YJ, Zheng CX, Lu YB, et al. Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application. Aging Cell. 2017;16:1083–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Martin P. Wound healing–aiming for perfect skin regeneration. Science. 1997;276:75–81.

    Article  CAS  PubMed  Google Scholar 

  4. Kim SY, Nair MG. Macrophages in wound healing: activation and plasticity. Immunol Cell Biol. 2019;97:258–67.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yoon D, Yoon D, Sim H, Hwang I, Lee JS, Chun W. Accelerated wound healing by fibroblasts differentiated from human embryonic stem cell-derived mesenchymal stem cells in a pressure ulcer animal model. Stem Cells Int. 2018;2018:4789568.

    PubMed  PubMed Central  Google Scholar 

  6. Kariminekoo S, Movassaghpour A, Rahimzadeh A, Talebi M, Shamsasenjan K, Akbarzadeh A. Implications of mesenchymal stem cells in regenerative medicine. Artif Cells Nanomed Biotechnol. 2016;44:749–57.

    Article  CAS  PubMed  Google Scholar 

  7. Gadelkarim M, Abushouk AI, Ghanem E, Hamaad AM, Saad AM, Abdel-Daim MM. Adipose-derived stem cells: effectiveness and advances in delivery in diabetic wound healing. Biomed Pharmacother. 2018;107:625–33.

    Article  CAS  PubMed  Google Scholar 

  8. Liu X, Wang S, Wu S, Hao Q, Li Y, Guo Z, et al. Exosomes secreted by adipose-derived mesenchymal stem cells regulate type I collagen metabolism in fibroblasts from women with stress urinary incontinence. Stem Cell Res Ther. 2018;9:159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mendt M, Rezvani K, Shpall E. Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant. 2019;54:789–92.

    Article  PubMed  Google Scholar 

  10. Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther. 2015;23:812–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6:481–92.

    Article  PubMed  Google Scholar 

  12. Ko KW, Yoo YI, Kim JY, Choi B, Park SB, Park W, et al. Attenuation of tumor necrosis factor-α induced inflammation by umbilical cord-mesenchymal stem cell derived exosome-mimetic nanovesicles in endothelial cells. Tissue Eng Regen Med. 2020;17:155–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Van Badiavas E. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev. 2015;24:1635–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Han Y, Jia L, Zheng Y, Li W. Salivary exosomes: emerging roles in systemic disease. Int J Biol Sci. 2018;14:633–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2015;77:13–27.

    Article  CAS  PubMed  Google Scholar 

  16. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32:252–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhou YF, Bosch-Marce M, Okuyama H, Krishnamachary B, Kimura H, Zhang L, et al. Spontaneous transformation of cultured mouse bone marrow-derived stromal cells. Cancer Res. 2006;66:10849–54.

    Article  CAS  PubMed  Google Scholar 

  18. Jiang L, Zhang S, Hu H, Yang J, Wang X, Ma Y, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate acute liver failure by reducing the activity of the NLRP3 inflammasome in macrophages. Biochem Biophys Res Commun. 2019;508:735–41.

    Article  CAS  PubMed  Google Scholar 

  19. Bjørge IM, Kim SY, Mano JF, Kalionis B, Chrzanowski W. Extracellular vesicles, exosomes and shedding vesicles in regenerative medicine—a new paradigm for tissue repair. Biomater Sci. 2017;6:60–78.

    Article  PubMed  Google Scholar 

  20. Goodarzi P, Larijani B, Alavi-Moghadam S, Tayanloo-Beik A, Mohamadi-Jahani F, Ranjbaran N, et al. Mesenchymal stem cells-derived exosomes for wound regeneration. Adv Exp Med Biol. 2018;1119:119–31.

    Article  CAS  PubMed  Google Scholar 

  21. Heo JS, Choi Y, Kim HO. Adipose-derived mesenchymal stem cells promote M2 macrophage phenotype through exosomes. Stem Cells Int. 2019;2019:7921760.

    PubMed  PubMed Central  Google Scholar 

  22. Li X, Li D, Wikstrom JD, Pivarcsi A, Sonkoly E, Stahle M, et al. MicroRNA-132 promotes fibroblast migration via regulating RAS p21 protein activator 1 in skin wound healing. Sci Rep. 2017;7:7797.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Essandoh K, Li Y, Huo J, Fan GC. MiRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response. Shock. 2016;46:122–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Herter EK, Xu Landén N. Non-coding RNAs: new players in skin wound healing. Adv Wound Care (New Rochelle). 2017;6:93–107.

    Article  Google Scholar 

  25. Mulholland EJ, Dunne N, McCarthy HO. MicroRNA as therapeutic targets for chronic wound healing. Mol Ther Nucleic Acids. 2017;8:46–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. He X, Dong Z, Cao Y, Wang H, Liu S, Liao L, et al. MSC-derived exosome promotes M2 polarization and enhances cutaneous wound healing. Stem Cells Int. 2019;2019:7132708.

    PubMed  PubMed Central  Google Scholar 

  27. Roşca AM, Ţuţuianu R, Titorencu ID. Mesenchymal stromal cells derived exosomes as tools for chronic wound healing therapy. Rom J Morphol Embryol. 2018;59:655–62.

    PubMed  Google Scholar 

  28. Zhong S, He X, Li Y, Lou X. Conditioned medium enhances osteogenic differentiation of induced pluripotent stem cell-derived mesenchymal stem cells. Tissue Eng Regen Med. 2019;16:141–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Blazquez R, Sanchez-Margallo FM, de la Rosa O, Dalemans W, Alvarez V, Tarazona R, et al. Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Front Immunol. 2014;5:556.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Li P, Guo X. A review: therapeutic potential of adipose-derived stem cells in cutaneous wound healing and regeneration. Stem Cell Res Ther. 2018;9:302.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Che Y, Shi X, Shi Y, Jiang X, Ai Q, Shi Y, et al. Exosomes derived from miR-143-overexpressing MSCs inhibit cell migration and invasion in human prostate cancer by downregulating TFF3. Mol Ther Nucleic Acids. 2019;18:232–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Morales-Kastresana A, Telford B, Musich TA, McKinnon K, Clayborne C, Braig Z, et al. Labeling extracellular vesicles for nanoscale flow cytometry. Sci Rep. 2017;7:1878.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Serra MB, Barroso WA, da Silva NN, Silva SDN, Borges ACR, Abreu IC, et al. From inflammation to current and alternative therapies involved in wound healing. Int J Inflam. 2017;2017:3406215.

    PubMed  PubMed Central  Google Scholar 

  34. Shah JM, Omar E, Pai DR, Sood S. Cellular events and biomarkers of wound healing. Indian J Plast Surg. 2012;45:220–8.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol. 2018;9:419.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Darby IA, Laverdet B, Bonté F, Desmoulière A. Fibroblasts and myofibroblasts in wound healing. Clin Cosmet Investig Dermatol. 2014;7:301–11.

    PubMed  PubMed Central  Google Scholar 

  37. Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009;284:34342–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci. 2019;26:78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Burrello J, Monticone S, Gai C, Gomez Y, Kholia S, Camussi G. Stem cell-derived extracellular vesicles and immune-modulation. Front Cell Dev Biol. 2016;4:83.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Domenis R, Cifù A, Quaglia S, Pistis C, Moretti M, Vicario A, et al. Pro inflammatory stimuli enhance the immunosuppressive functions of adipose mesenchymal stem cells-derived exosomes. Sci Rep. 2018;8:13325.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Banerjee J, Sen CK. microRNA and wound healing. Adv Exp Med Biol. 2015;888:291–305.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Ti D, Hao H, Fu X, Han W. Mesenchymal stem cells-derived exosomal microRNAs contribute to wound inflammation. Sci China Life Sci. 2016;59:1305–12.

    Article  CAS  PubMed  Google Scholar 

  43. Primo MN, Bak RO, Schibler B, Mikkelsen JG. Regulation of pro-inflammatory cytokines TNFalpha and IL24 by microRNA-203 in primary keratinocytes. Cytokine. 2012;60:741–8.

    Article  CAS  PubMed  Google Scholar 

  44. Huang C, Liu XJ, QunZhou XJ, Xie J, Ma TT, Meng XM, et al. MiR-146a modulates macrophage polarization by inhibiting Notch1 pathway in RAW264.7 macrophages. Int Immunopharmacol. 2016;32:46–54.

    Article  PubMed  CAS  Google Scholar 

  45. Kato M, Zhang J, Wang M, Lanting L, Yuan H, Rossi JJ, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A. 2007;104:3432–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A. 2008;105:13027–32.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wang B, Herman-Edelstein M, Koh P, Burns W, Jandeleit-Dahm K, Watson A, et al. E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta. Diabetes. 2010;59:1794–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgement

This research was funded by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIT) (No. 2019R1C1C1007036).

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Correspondence to Seung Yong Song or Hyun Ok Kim.

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The study was approved by the Institutional Review Board at Severance Hospital (IRB No. 4-2019-0060).

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Heo, J.S., Kim, S., Yang, C.E. et al. Human Adipose Mesenchymal Stem Cell-Derived Exosomes: A Key Player in Wound Healing. Tissue Eng Regen Med 18, 537–548 (2021). https://doi.org/10.1007/s13770-020-00316-x

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  • DOI: https://doi.org/10.1007/s13770-020-00316-x

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