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Endocrine, Metabolic & Immune Disorders - Drug Targets

Author(s): Qing-Hua Xiong, Lei Zhao, Guan-Qun Wan, Yun-Gang Hu and Xiao-Lin Li*

DOI: 10.2174/1871530322666220523151713

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Engineered BMSCs-Derived Exosomal miR-542-3p Promotes Cutaneous Wound Healing

Page: [336 - 346] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: The healing of cutaneous wounds requires better strategies, which remain a challenge. Previous reports indicated that the therapeutic function of mesenchymal stem cells is mediated by exosomes. This work demonstrated the regenerative effects of engineered BMSCsderived Exosomal miR-542-3p in skin wound mouse models.

Methods: Bone marrow mesenchymal stem cells (BMSCs) -derived exosomes (BMSCs-Exos) were isolated by ultracentrifugation and identified by Transmission Electron Microscope (TEM) and Nanoparticle Tracking Analysis (NTA). BMSCs-Exo was loaded with miRNA-542-3p by electroporation. We explored the effects of miRNA-542-3p-Exo on the proliferation and migration of Human Skin Fibroblasts (HSFs)/Human dermal microvascular endothelial cells (HMECs). In addition, The angiogenesis of HMECs was detected by Tube formation assay in vitro. The effects of miRNA-542-3p-Exo in the skin wound mouse model were detected by H&E staining, Masson staining, and immunofluorescence analysis. We assessed the effect of miRNA-542-3p-Exo on collagen deposition, new blood vessel formation, and wound remodeling in a skin wound mouse model.

Results: MiRNA-542-3p-Exos could be internalized by HSFs/HMECs and enhance the proliferation, migration, and angiogenesis of HSFs/HMECs in vitro and in vivo. The protein expression of collagen1/3 was significantly increased after miRNA-542-3p-Exo treatment in HSFs. In addition, the local injection of miRNA-542-3p-Exo promoted cellular proliferation, collagen deposition, neovascularization, and accelerated wound closure.

Conclusion: This study suggested that miRNA-542-3p-Exo can stimulate HSFs/HMECs function. The treatment of miRNA-542-3p-Exo in the skin wound mouse model significantly promotes wound repair. The therapeutic potential of miRNA-542-3p-Exo may be a future therapeutic strategy for cutaneous wound healing.

Keywords: Bone marrow mesenchymal stem cells (BMSCs), exosomes, miRNA-542-3p, wound healing, HMECs, NTA.

Graphical Abstract

[1]
van Zanten, M.C.; Mistry, R.M.; Suami, H.; Campbell-Lloyd, A.; Finkemeyer, J.P.; Piller, N.B.; Caplash, Y. The lymphatic response to injury with soft-tissue reconstruction in high-energy open tibial fractures of the lower extremity. Plast. Reconstr. Surg., 2017, 139(2), 483-491.
[http://dx.doi.org/10.1097/PRS.0000000000003024] [PMID: 28125537]
[2]
Barbier, O.; Pasquier, P. Wound irrigation in initial management of open fractures. N. Engl. J. Med., 2016, 374(18), 1788-1789.
[http://dx.doi.org/10.1056/NEJMc1601157] [PMID: 27144861]
[3]
Falanga, V. Wound healing and its impairment in the diabetic foot. Lancet, 2005, 366(9498), 1736-1743.
[http://dx.doi.org/10.1016/S0140-6736(05)67700-8] [PMID: 16291068]
[4]
Plikus, M.V.; Guerrero-Juarez, C.F.; Ito, M.; Li, Y.R.; Dedhia, P.H.; Zheng, Y.; Shao, M.; Gay, D.L.; Ramos, R.; Hsi, T.C.; Oh, J.W.; Wang, X.; Ramirez, A.; Konopelski, S.E.; Elzein, A.; Wang, A.; Supapannachart, R.J.; Lee, H.L.; Lim, C.H.; Nace, A.; Guo, A.; Treffeisen, E.; Andl, T.; Ramirez, R.N.; Murad, R.; Offermanns, S.; Metzger, D.; Chambon, P.; Widgerow, A.D.; Tuan, T.L.; Mortazavi, A.; Gupta, R.K.; Hamilton, B.A.; Millar, S.E.; Seale, P.; Pear, W.S.; Lazar, M.A.; Cotsarelis, G. Regeneration of fat cells from myofibroblasts during wound healing. Science, 2017, 355(6326), 748-752.
[http://dx.doi.org/10.1126/science.aai8792] [PMID: 28059714]
[5]
Heublein, H.; Bader, A.; Giri, S. Preclinical and clinical evidence for stem cell therapies as treatment for diabetic wounds. Drug Discov. Today, 2015, 20(6), 703-717.
[http://dx.doi.org/10.1016/j.drudis.2015.01.005] [PMID: 25603421]
[6]
Duscher, D.; Barrera, J.; Wong, V.W.; Maan, Z.N.; Whittam, A.J.; Januszyk, M.; Gurtner, G.C. Stem cells in wound healing: The future of regenerative medicine? A mini-review. Gerontology, 2016, 62(2), 216-225.
[http://dx.doi.org/10.1159/000381877] [PMID: 26045256]
[7]
Amariglio, N.; Hirshberg, A.; Scheithauer, B.W.; Cohen, Y.; Loewenthal, R.; Trakhtenbrot, L.; Paz, N.; Koren-Michowitz, M.; Waldman, D.; Leider-Trejo, L.; Toren, A.; Constantini, S.; Rechavi, G. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med., 2009, 6(2), e1000029.
[http://dx.doi.org/10.1371/journal.pmed.1000029] [PMID: 19226183]
[8]
Meier, E.R. Treatment options for sickle cell disease. Pediatr. Clin. North Am., 2018, 65(3), 427-443.
[http://dx.doi.org/10.1016/j.pcl.2018.01.005] [PMID: 29803275]
[9]
Herberts, C.A.; Kwa, M.S.; Hermsen, H.P. Risk factors in the development of stem cell therapy. J. Transl. Med., 2011, 9(1), 29.
[http://dx.doi.org/10.1186/1479-5876-9-29] [PMID: 21418664]
[10]
Cabral, J.; Ryan, A.E.; Griffin, M.D.; Ritter, T. Extracellular vesicles as modulators of wound healing. Adv. Drug Deliv. Rev., 2018, 129, 394-406.
[http://dx.doi.org/10.1016/j.addr.2018.01.018] [PMID: 29408181]
[11]
Qiu, G.; Zheng, G.; Ge, M.; Wang, J.; Huang, R.; Shu, Q.; Xu, J. Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs. Stem Cell Res. Ther., 2018, 9(1), 320.
[http://dx.doi.org/10.1186/s13287-018-1069-9] [PMID: 30463593]
[12]
Tian, T.; Zhu, Y.L.; Zhou, Y.Y.; Liang, G.F.; Wang, Y.Y.; Hu, F.H.; Xiao, Z.D. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J. Biol. Chem., 2014, 289(32), 22258-22267.
[http://dx.doi.org/10.1074/jbc.M114.588046] [PMID: 24951588]
[13]
Liang, X.; Zhang, L.; Wang, S.; Han, Q.; Zhao, R.C. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J. Cell Sci., 2016, 129(11), 2182-2189.
[http://dx.doi.org/10.1242/jcs.170373] [PMID: 27252357]
[14]
Hu, L.; Wang, J.; Zhou, X.; Xiong, Z.; Zhao, J.; Yu, R.; Huang, F.; Zhang, H.; Chen, L. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci. Rep., 2016, 6(1), 32993.
[http://dx.doi.org/10.1038/srep32993] [PMID: 27615560]
[15]
Martin, P. Wound healing-aiming for perfect skin regeneration. Science, 1997, 276(5309), 75-81.
[http://dx.doi.org/10.1126/science.276.5309.75] [PMID: 9082989]
[16]
Tkach, M.; Théry, C. Communication by extracellular vesicles: Where we are and where we need to go. Cell, 2016, 164(6), 1226-1232.
[http://dx.doi.org/10.1016/j.cell.2016.01.043] [PMID: 26967288]
[17]
Mulcahy, L.A.; Pink, R.C.; Carter, D.R. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles, 2014, 3(1), 3.
[http://dx.doi.org/10.3402/jev.v3.24641] [PMID: 25143819]
[18]
Lu, Z.; Wang, S.; Zhu, X.; Yuan, X.; Zhan, Y.; Li, Y.; Wang, W. Resveratrol induces endothelial progenitor cells angiogenesis via MiR-542-3p by targeting angiopoietin-2 and involves in recanalization of venous thrombosis. Med. Sci. Monit., 2019, 25, 7675-7683.
[http://dx.doi.org/10.12659/MSM.917013] [PMID: 31606730]
[19]
He, T.; Qi, F.; Jia, L.; Wang, S.; Wang, C.; Song, N.; Fu, Y.; Li, L.; Luo, Y. Tumor cell-secreted angiogenin induces angiogenic activity of endothelial cells by suppressing miR-542-3p. Cancer Lett., 2015, 368(1), 115-125.
[http://dx.doi.org/10.1016/j.canlet.2015.07.036] [PMID: 26272182]
[20]
Vahidi Manesh, P.; Farazmand, A.; Gharibdoost, F.; Vanaki, N.; Mostafaei, S.; Kavosi, H.; Mahmoudi, M.B.; Mahmoudi, M. Downregulation of miR-542-3p contributes to apoptosis resistance in dermal fibroblasts from systemic sclerosis patients via survivin overexpression. Iran. J. Allergy Asthma Immunol., 2019, 18(2), 173-181.
[http://dx.doi.org/10.18502/ijaai.v18i2.920] [PMID: 31066253]
[21]
Hellmann, J.; Sansbury, B.E.; Wong, B.; Li, X.; Singh, M.; Nuutila, K.; Chiang, N.; Eriksson, E.; Serhan, C.N.; Spite, M. Biosynthesis of D-series resolvins in skin provides insights into their role in tissue repair. J. Invest. Dermatol., 2018, 138(9), 2051-2060.
[http://dx.doi.org/10.1016/j.jid.2018.03.1498] [PMID: 29559341]
[22]
Ud-Din, S.; Foden, P.; Mazhari, M.; Al-Habba, S.; Baguneid, M.; Bulfone-Paus, S.; McGeorge, D.; Bayat, A. A double-blind, randomized trial shows the role of zonal priming and direct topical application of epigallocatechin-3-gallate in the modulation of cutaneous scarring in human skin. J. Invest. Dermatol., 2019, 139(8), 1680-1690.e16.
[http://dx.doi.org/10.1016/j.jid.2019.01.030] [PMID: 30822414]
[23]
Walocko, F.M.; Eber, A.E.; Kirsner, R.S.; Badiavas, E.; Nouri, K. Systematic review of the therapeutic roles of adipose tissue in dermatology. J. Am. Acad. Dermatol., 2018, 79(5), 935-944.
[http://dx.doi.org/10.1016/j.jaad.2018.06.010] [PMID: 29902544]
[24]
Qu, Y.; Luan, J. Extracellular vesicles from human adipose-derived stem cells for the improvement of angiogenesis and fat-grafting application. Plast. Reconstr. Surg., 2020, 146(1), 104e-105e.
[http://dx.doi.org/10.1097/PRS.0000000000006046] [PMID: 31568294]
[25]
Wood, M.J.; O’Loughlin, A.J.; Samira, L. Exosomes and the blood-brain barrier: Implications for neurological diseases. Ther. Deliv., 2011, 2(9), 1095-1099.
[http://dx.doi.org/10.4155/tde.11.83] [PMID: 22833906]
[26]
Saint-Pol, J.; Gosselet, F.; Duban-Deweer, S.; Pottiez, G.; Karamanos, Y. Targeting and crossing the blood-brain barrier with extracellular vesicles. Cells, 2020, 9(4), E851.
[http://dx.doi.org/10.3390/cells9040851] [PMID: 32244730]
[27]
Xiong, Y.; Mahmood, A.; Chopp, M. Emerging potential of exosomes for treatment of traumatic brain injury. Neural Regen. Res., 2017, 12(1), 19-22.
[http://dx.doi.org/10.4103/1673-5374.198966] [PMID: 28250732]
[28]
Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M.J. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol., 2011, 29(4), 341-345.
[http://dx.doi.org/10.1038/nbt.1807] [PMID: 21423189]
[29]
Hung, M.E.; Leonard, J.N. A platform for actively loading cargo RNA to elucidate limiting steps in EV-mediated delivery. J. Extracell. Vesicles, 2016, 5(1), 31027.
[http://dx.doi.org/10.3402/jev.v5.31027] [PMID: 27189348]
[30]
Cai, G.; Cai, G.; Zhou, H.; Zhuang, Z.; Liu, K.; Pei, S.; Wang, Y.; Wang, H.; Wang, X.; Xu, S.; Cui, C.; Sun, M.; Guo, S.; Jia, K.; Wang, X.; Zhang, D. Mesenchymal stem cell-derived exosome miR-542-3p suppresses inflammation and prevents cerebral infarction. Stem Cell Res. Ther., 2021, 12(1), 2.
[http://dx.doi.org/10.1186/s13287-020-02030-w] [PMID: 33407827]
[31]
Driskell, R.R.; Lichtenberger, B.M.; Hoste, E.; Kretzschmar, K.; Simons, B.D.; Charalambous, M.; Ferron, S.R.; Herault, Y.; Pavlovic, G.; Ferguson-Smith, A.C.; Watt, F.M. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature, 2013, 504(7479), 277-281.
[http://dx.doi.org/10.1038/nature12783] [PMID: 24336287]
[32]
Martin, J.M.; Zenilman, J.M.; Lazarus, G.S. Molecular microbiology: New dimensions for cutaneous biology and wound healing. J. Invest. Dermatol., 2010, 130(1), 38-48.
[http://dx.doi.org/10.1038/jid.2009.221] [PMID: 19626034]