Extracellular Vesicles Isolated from Mesenchymal Stromal Cells Primed with Hypoxia: Novel Strategy in Regenerative Medicine

Shalmali       Pendse; Vaijayanti       Kale; Anuradha       Vaidya
doi:10.2174/1574888X15999200918110638
Abstract

Mesenchymal stromal cells (MSCs) regulate other cell types through a strong paracrine component called the secretome, comprising several bioactive entities. The composition of the MSCs’ secretome is dependent upon the microenvironment in which they thrive, and hence, it could be altered by pre-conditioning the MSCs during in vitro culture. The primary aim of this review is to discuss various strategies that are being used for the pre-conditioning of MSCs, also known as “priming of MSCs”, in the context of improving their therapeutic potential. Several studies have underscored the importance of extracellular vesicles (EVs) derived from primed MSCs in improving their efficacy for the treatment of various diseases. We have previously shown that co-culturing hematopoietic stem cells (HSCs) with hypoxia-primed MSCs improves their engraftment potential. Now the question we pose is, would priming of MSCs with hypoxia favorably alter their secretome? and would this altered secretome work as effectively as the cell to cell contact did? Here we review the current strategies of using the secretome, specifically the EVs (microvesicles and exosomes), collected from the primed MSCs with the intention of expanding HSCs ex vivo. We speculate that effective priming of MSCs in vitro could modulate the molecular profile of their secretome, which could eventually be used as a cell-free biologic in clinical settings.
Keywords: Mesenchymal stromal cells, extracellular vesicles, microvesicles, exosomes, hypoxia, regenerative medicine.
« Previous Next »
[1] 
Pashoutan Sarvar D, Shamsasenjan K, Akbarzadehlaleh P. Mesenchymal stem cell-derived exosomes: New opportunity in cell-free therapy. Adv Pharm Bull  2016; 6(3): 293-9.
[http://dx.doi.org/10.15171/apb.2016.041] [PMID: 27766213] 
[2] 
Stik G, Crequit S, Petit L, et al. Extracellular vesicles of stromal origin target and support hematopoietic stem and progenitor cells. J Cell Biol  2017; 216(7): 2217-30.
[http://dx.doi.org/10.1083/jcb.201601109] [PMID: 28630143] 
[3] 
Aqmasheh S, Shamsasanjan K, Akbarzadehlaleh P, Pashoutan Sarvar D, Timari H. Effects of mesenchymal stem cell derivatives on hematopoiesis and hematopoietic stem cells. Adv Pharm Bull  2017; 7(2): 165-77.
[http://dx.doi.org/10.15171/apb.2017.021] [PMID: 28761818] 
[4] 
Fitzsimmons REB, Mazurek MS, Soos A, Simmons CA. Mesenchymal stromal/stem cells in regenerative medicine and tissue engineering. Stem Cells Int  2018; 2018: 8031718.
[http://dx.doi.org/10.1155/2018/8031718] [PMID: 30210552] 
[5] 
Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: Toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci  2017; 18(9): 1852.
[http://dx.doi.org/10.3390/ijms18091852] [PMID: 28841158] 
[6] 
Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: Revisiting history, concepts, and assays. Cell Stem Cell  2008; 2(4): 313-9.
[http://dx.doi.org/10.1016/j.stem.2008.03.002] [PMID: 18397751] 
[7] 
Vaidya A, Kale V. Hematopoietic stem cells, their niche, and the concept of co-culture systems: A critical review. J Stem Cells  2015; 10(1): 13-31.
[PMID: 26665935] 
[8] 
Lindner U, Kramer J, Rohwedel J, Schlenke P. Mesenchymal stem or stromal cells: Toward a better understanding of their biology? Transfus Med Hemother  2010; 37(2): 75-83.
[http://dx.doi.org/10.1159/000290897] [PMID: 20737049] 
[9] 
Sipp D, Robey PG, Turner L. Clear up this stem-cell mess. Nature  2018; 561(7724): 455-7.
[http://dx.doi.org/10.1038/d41586-018-06756-9] [PMID: 30258150] 
[10] 
Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy  2006; 8(4): 315-7.
[http://dx.doi.org/10.1080/14653240600855905] [PMID: 16923606] 
[11] 
Battiwalla M, Hematti P. Mesenchymal stem cells in hematopoietic stem cell transplantation. Cytotherapy  2009; 11(5): 503-15.
[http://dx.doi.org/10.1080/14653240903193806] [PMID: 19728189] 
[12] 
Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration. Cytotherapy  2016; 18(1): 13-24.
[http://dx.doi.org/10.1016/j.jcyt.2015.10.008] [PMID: 26631828] 
[13] 
Zhao K, Liu Q. The clinical application of mesenchymal stromal cells in hematopoietic stem cell transplantation. J Hematol Oncol  2016; 9(1): 46.
[http://dx.doi.org/10.1186/s13045-016-0276-z] [PMID: 27193054] 
[14] 
Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Gonçalves RM. Mesenchymal stromal cell secretome: Influencing therapeutic potential by cellular pre-conditioning. Front Immunol  2018; 9: 2837.
[http://dx.doi.org/10.3389/fimmu.2018.02837] [PMID: 30564236] 
[15] 
Guerrouahen BS, Sidahmed H, Al Sulaiti A, Al Khulaifi M, Cugno C. Enhancing mesenchymal stromal cell immunomodulation for treating conditions influenced by the immune system. Stem Cells Int  2019; 2019: 7219297.
[http://dx.doi.org/10.1155/2019/7219297] [PMID: 31467564] 
[16] 
Teixeira FG, Salgado AJ. Mesenchymal stem cells secretome: current trends and future challenges. Neural Regen Res  2020; 15(1): 75-7.
[http://dx.doi.org/10.4103/1673-5374.264455] [PMID: 31535654] 
[17] 
Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal stem cells for regenerative medicine. Cells  2019; 8(8): 886.
[http://dx.doi.org/10.3390/cells8080886] [PMID: 31412678] 
[18] 
Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther  2016; 7(1): 125.
[http://dx.doi.org/10.1186/s13287-016-0363-7] [PMID: 27581859] 
[19] 
Driscoll J, Patel T. The mesenchymal stem cell secretome as an acellular regenerative therapy for liver disease. J Gastroenterol  2019; 54(9): 763-73.
[http://dx.doi.org/10.1007/s00535-019-01599-1] [PMID: 31270691] 
[20] 
Andrzejewska A, Lukomska B, Janowski M. Concise review: Mesenchymal stem cells: From roots to boost. Stem Cells  2019; 37(7): 855-64.
[http://dx.doi.org/10.1002/stem.3016] [PMID: 30977255] 
[21] 
Fernández-García M, Yañez RM, Sánchez-Domínguez R, et al. Mesenchymal stromal cells enhance the engraftment of hematopoietic stem cells in an autologous mouse transplantation model. Stem Cell Res Ther  2015; 6(1): 165.
[http://dx.doi.org/10.1186/s13287-015-0155-5] [PMID: 26345192] 
[22] 
Le Blanc K, Samuelsson H, Gustafsson B, et al. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia  2007; 21(8): 1733-8.
[http://dx.doi.org/10.1038/sj.leu.2404777] [PMID: 17541394] 
[23] 
Liu FD, Tam K, Pishesha N, Poon Z, Van Vliet KJ. Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome. Stem Cell Res Ther  2018; 9(1): 268.
[http://dx.doi.org/10.1186/s13287-018-0982-2] [PMID: 30352620] 
[24] 
Noronha NC, Mizukami A, Caliári-Oliveira C, et al. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther  2019; 10(1): 131.
[http://dx.doi.org/10.1186/s13287-019-1224-y] [PMID: 31046833] 
[25] 
Haque N, Kasim NH, Rahman MT. Optimization of pre-transplantation conditions to enhance the efficacy of mesenchymal stem cells. Int J Biol Sci  2015; 11(3): 324-34.
[http://dx.doi.org/10.7150/ijbs.10567] [PMID: 25678851] 
[26] 
Kale VP. Application of “primed” Mesenchymal Stromal Cells in hematopoietic stem cell transplantation: Current status and Future prospects. Stem Cells Dev  2019; 28(22): 1473-9.
[http://dx.doi.org/10.1089/scd.2019.0149] [PMID: 31559908] 
[27] 
Philipp D, Suhr L, Wahlers T, Choi YH, Paunel-Görgülü A. Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization. Stem Cell Res Ther  2018; 9(1): 286.
[http://dx.doi.org/10.1186/s13287-018-1039-2] [PMID: 30359316] 
[28] 
Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WC. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem Cells Int  2016; 2016: 3924858.
[http://dx.doi.org/10.1155/2016/3924858] [PMID: 27822228] 
[29] 
Lee MW, Ryu S, Kim DS, Sung KW, Koo HH, Yoo KH. Strategies to improve the immunosuppressive properties of human mesenchymal stem cells. Stem Cell Res Ther  2015; 6(1): 179.
[http://dx.doi.org/10.1186/s13287-015-0178-y] [PMID: 26445096] 
[30] 
Polchert D, Sobinsky J, Douglas G, et al. IFN-γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol  2008; 38(6): 1745-55.
[http://dx.doi.org/10.1002/eji.200738129] [PMID: 18493986] 
[31] 
Sart S, Ma T, Li Y. Preconditioning stem cells for in vivo delivery. Biores Open Access  2014; 3(4): 137-49.
[http://dx.doi.org/10.1089/biores.2014.0012] [PMID: 25126478] 
[32] 
Regmi S, Pathak S, Kim JO, Yong CS, Jeong JH. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur J Cell Biol  2019; 98(5-8): 151041.
[http://dx.doi.org/10.1016/j.ejcb.2019.04.002] [PMID: 31023504] 
[33] 
Waszak P, Alphonse R, Vadivel A, Ionescu L, Eaton F, Thébaud B. Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem Cells Dev  2012; 21(15): 2789-97.
[http://dx.doi.org/10.1089/scd.2010.0566] [PMID: 22533467] 
[34] 
Luo R, Lu Y, Liu J, Cheng J, Chen Y. Enhancement of the efficacy of mesenchymal stem cells in the treatment of ischemic diseases. Biomed Pharmacother  2019; 109: 2022-34.
[http://dx.doi.org/10.1016/j.biopha.2018.11.068] [PMID: 30551458] 
[35] 
Hu C, Li L. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J Cell Mol Med  2018; 22(3): 1428-42.
[http://dx.doi.org/10.1111/jcmm.13492] [PMID: 29392844] 
[36] 
Luk F, Carreras-Planella L, Korevaar SS, et al. Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function. Front Immunol  2017; 8: 1042.
[http://dx.doi.org/10.3389/fimmu.2017.01042] [PMID: 28894451] 
[37] 
van Zoelen EJ, Duarte I, Hendriks JM, van der Woning SP. TGFβ-induced switch from adipogenic to osteogenic differentiation of human mesenchymal stem cells: Identification of drug targets for prevention of fat cell differentiation. Stem Cell Res Ther  2016; 7(1): 123.
[http://dx.doi.org/10.1186/s13287-016-0375-3] [PMID: 27562730] 
[38] 
Lu Z, Wang G, Dunstan CR, et al. Activation and promotion of adipose stem cells by tumour necrosis factor-α preconditioning for bone regeneration. J Cell Physiol  2013; 228(8): 1737-44.
[http://dx.doi.org/10.1002/jcp.24330] [PMID: 23359411] 
[39] 
Carrero R, Cerrada I, Lledó E, et al. IL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-κB. Stem Cell Rev Rep  2012; 8(3): 905-16.
[http://dx.doi.org/10.1007/s12015-012-9364-9] [PMID: 22467443] 
[40] 
Sullivan CB, Porter RM, Evans CH, et al. TNFα and IL-1β influence the differentiation and migration of murine MSCs independently of the NF-κB pathway. Stem Cell Res Ther  2014; 5(4): 104.
[http://dx.doi.org/10.1186/scrt492] [PMID: 25163844] 
[41] 
Pasha Z, Wang Y, Sheikh R, Zhang D, Zhao T, Ashraf M. Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc Res  2008; 77(1): 134-42.
[http://dx.doi.org/10.1093/cvr/cvm025] [PMID: 18006467] 
[42] 
Tang Y, Cai B, Yuan F, et al. Melatonin pretreatment improves the survival and function of transplanted mesenchymal stem cells after focal cerebral ischemia. Cell Transplant  2014; 23(10): 1279-91.
[http://dx.doi.org/10.3727/096368913X667510] [PMID: 23635511] 
[43] 
Yao Y, Zhang F, Wang L, et al. Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction. J Biomed Sci  2009; 16(1): 74.
[http://dx.doi.org/10.1186/1423-0127-16-74] [PMID: 19691857] 
[44] 
Kim DS, Jang IK, Lee MW, et al. Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-γ. EBioMedicine  2018; 28: 261-73.
[http://dx.doi.org/10.1016/j.ebiom.2018.01.002] [PMID: 29366627] 
[45] 
Park A, Park H, Yoon J, et al. Priming with Toll-like receptor 3 agonist or interferon-gamma enhances the therapeutic effects of human mesenchymal stem cells in a murine model of atopic dermatitis. Stem Cell Res Ther  2019; 10(1): 66.
[http://dx.doi.org/10.1186/s13287-019-1164-6] [PMID: 30795812] 
[46] 
Vigo T, La Rocca C, Faicchia D, et al. IFNβ enhances mesenchymal stromal (Stem) cells immunomodulatory function through STAT1-3 activation and mTOR-associated promotion of glucose metabolism. Cell Death Dis  2019; 10(2): 85.
[http://dx.doi.org/10.1038/s41419-019-1336-4] [PMID: 30692524] 
[47] 
Tu Z, Li Q, Bu H, Lin F. Mesenchymal stem cells inhibit complement activation by secreting factor H. Stem Cells Dev  2010; 19(11): 1803-9.
[http://dx.doi.org/10.1089/scd.2009.0418] [PMID: 20163251] 
[48] 
Barrachina L, Remacha AR, Romero A, et al. Priming equine bone marrow-derived mesenchymal stem cells with proinflammatory cytokines: implications in immunomodulation–immunogenicity balance, cell viability, and differentiation potential. Stem Cells Dev  2017; 26(1): 15-24.
[http://dx.doi.org/10.1089/scd.2016.0209] [PMID: 27712399] 
[49] 
Yu Y, Yoo SM, Park HH, et al. Preconditioning with interleukin-1 beta and interferon-gamma enhances the efficacy of human umbilical cord blood-derived mesenchymal stem cells-based therapy via enhancing prostaglandin E2 secretion and indoleamine 2,3-dioxygenase activity in dextran sulfate sodium-induced colitis. J Tissue Eng Regen Med  2019; 13(10): 1792-804.
[http://dx.doi.org/10.1002/term.2930] [PMID: 31293088] 
[50] 
Redondo-Castro E, Cunningham C, Miller J, et al. Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro. Stem Cell Res Ther  2017; 8(1): 79.
[http://dx.doi.org/10.1186/s13287-017-0531-4] [PMID: 28412968] 
[51] 
Sivanathan KN, Rojas-Canales DM, Hope CM, et al. Interleukin-17A-induced human mesenchymal stem cells are superior modulators of immunological function. Stem Cells  2015; 33(9): 2850-63.
[http://dx.doi.org/10.1002/stem.2075] [PMID: 26037953] 
[52] 
Niu P, Smagul A, Wang L, et al. Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence. Oncotarget  2015; 6(20): 17938-57.
[http://dx.doi.org/10.18632/oncotarget.4852] [PMID: 26255627] 
[53] 
Wang M, Cai J, Huang F, et al. Pre-treatment of human umbilical cord-derived mesenchymal stem cells with interleukin-6 abolishes their growth-promoting effect on gastric cancer cells. Int J Mol Med  2015; 35(2): 367-75.
[http://dx.doi.org/10.3892/ijmm.2014.2019] [PMID: 25483835] 
[54] 
Mead B, Chamling X, Zack DJ, Ahmed Z, Tomarev S. TNFα-mediated priming of mesenchymal stem cells enhances their neuroprotective effect on retinal ganglion cells. Invest Ophthalmol Vis Sci  2020; 61(2): 6.
[http://dx.doi.org/10.1167/iovs.61.2.6] [PMID: 32031578] 
[55] 
Park BW, Jung SH, Das S, et al. In vivo priming of human mesenchymal stem cells with hepatocyte growth factor-engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair. Sci Adv  2020; 6(13): eaay6994.
[http://dx.doi.org/10.1126/sciadv.aay6994] [PMID: 32284967] 
[56] 
Amin AH, Abd Elmageed ZY, Nair D, et al. Modified multipotent stromal cells with epidermal growth factor restore vasculogenesis and blood flow in ischemic hind-limb of type II diabetic mice. Lab Invest  2010; 90(7): 985-96.
[http://dx.doi.org/10.1038/labinvest.2010.86] [PMID: 20440273] 
[57] 
Xinaris C, Morigi M, Benedetti V, et al. A novel strategy to enhance mesenchymal stem cell migration capacity and promote tissue repair in an injury specific fashion. Cell Transplant  2013; 22(3): 423-36.
[http://dx.doi.org/10.3727/096368912X653246] [PMID: 22889699] 
[58] 
Hoke NN, Salloum FN, Kass DA, Das A, Kukreja RC. Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. Stem Cells  2012; 30(2): 326-35.
[http://dx.doi.org/10.1002/stem.789] [PMID: 22102597] 
[59] 
Lee HS, Kim KS, Lim HS, et al. Priming Wharton’s jelly-derived mesenchymal stromal/stem cells with ROCK inhibitor improves recovery in an intracerebral hemorrhage model. J Cell Biochem  2015; 116(2): 310-9.
[http://dx.doi.org/10.1002/jcb.24969] [PMID: 25185536] 
[60] 
Gharibi B, Farzadi S, Ghuman M, Hughes FJ. Inhibition of Akt/mTOR attenuates age-related changes in mesenchymal stem cells. Stem Cells  2014; 32(8): 2256-66.
[http://dx.doi.org/10.1002/stem.1709] [PMID: 24659476] 
[61] 
Kass DA, Champion HC, Beavo JA. Phosphodiesterase type 5: expanding roles in cardiovascular regulation. Circ Res  2007; 101(11): 1084-95.
[http://dx.doi.org/10.1161/CIRCRESAHA.107.162511] [PMID: 18040025] 
[62] 
Hassan F, Meduru S, Taguchi K, et al. Carvedilol enhances mesenchymal stem cell therapy for myocardial infarction via inhibition of caspase-3 expression. J Pharmacol Exp Ther  2012; 343(1): 62-71.
[http://dx.doi.org/10.1124/jpet.112.196915] [PMID: 22739507] 
[63] 
Chulpanova DS, Kitaeva KV, Tazetdinova LG, James V, Rizvanov AA, Solovyeva VV. Application of mesenchymal stem cells for therapeutic agent delivery in anti-tumor treatment. Front Pharmacol  2018; 9: 259.
[http://dx.doi.org/10.3389/fphar.2018.00259] [PMID: 29615915] 
[64] 
Pessina A, Bonomi A, Coccè V, et al. Mesenchymal stromal cells primed with paclitaxel provide a new approach for cancer therapy. PLoS One  2011; 6(12): e28321.
[http://dx.doi.org/10.1371/journal.pone.0028321] [PMID: 22205945] 
[65] 
Zhang B, Shan H, Li D, Li ZR, Zhu KS, Jiang ZB. The inhibitory effect of MSCs expressing TRAIL as a cellular delivery vehicle in combination with cisplatin on hepatocellular carcinoma. Cancer Biol Ther  2012; 13(12): 1175-84.
[http://dx.doi.org/10.4161/cbt.21347] [PMID: 22922789] 
[66] 
Zhang J, Hou L, Wu X, et al. Inhibitory effect of genetically engineered mesenchymal stem cells with Apoptin on hepatoma cells in vitro and in vivo. Mol Cell Biochem  2016; 416(1-2): 193-203.
[http://dx.doi.org/10.1007/s11010-016-2707-0] [PMID: 27142531] 
[67] 
Gjorgieva D, Zaidman N, Bosnakovski D. Mesenchymal stem cells for anti-cancer drug delivery. Recent Patents Anticancer Drug Discov  2013; 8(3): 310-8.
[http://dx.doi.org/10.2174/15748928113089990040] [PMID: 23688246] 
[68] 
Ejtehadifar M, Shamsasenjan K, Movassaghpour A, et al. The effect of hypoxia on mesenchymal stem cell biology. Adv Pharm Bull  2015; 5(2): 141-9.
[http://dx.doi.org/10.15171/apb.2015.021] [PMID: 26236651] 
[69] 
Masoud GN, Li W. HIF-1α pathway: Role, regulation and intervention for cancer therapy. Acta Pharm Sin B  2015; 5(5): 378-89.
[http://dx.doi.org/10.1016/j.apsb.2015.05.007] [PMID: 26579469] 
[70] 
Xia M, Huang R, Sun Y, et al. Identification of chemical compounds that induce HIF-1α activity. Toxicol Sci  2009; 112(1): 153-63.
[http://dx.doi.org/10.1093/toxsci/kfp123] [PMID: 19502547] 
[71] 
Imanirad P, Solaimani Kartalaei P, Crisan M, et al. HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo. Stem Cell Res (Amst)  2014; 12(1): 24-35.
[http://dx.doi.org/10.1016/j.scr.2013.09.006] [PMID: 24141110] 
[72] 
Zhang YB, Wang X, Meister EA, et al. The effects of CoCl2 on HIF-1α protein under experimental conditions of autoprogressive hypoxia using mouse models. Int J Mol Sci  2014; 15(6): 10999-1012.
[http://dx.doi.org/10.3390/ijms150610999] [PMID: 24945310] 
[73] 
Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab  2006; 3(3): 187-97.
[http://dx.doi.org/10.1016/j.cmet.2006.01.012] [PMID: 16517406] 
[74] 
Phelps J, Sanati-Nezhad A, Ungrin M, Duncan NA, Sen A. Bioprocessing of mesenchymal stem cells and their derivatives: Toward cell-free therapeutics. Stem Cells Int  2018; 2018: 9415367.
[http://dx.doi.org/10.1155/2018/9415367] [PMID: 30275839] 
[75] 
Bedessem B, Marie-Paule M, Hamel M, Giroud F, Stéphanou A. Effects of the hypoxia-mimetic agents DFO and CoCl2 on heLa-fucci cells. J Cell Biol Cell Metab  2015; 2(004)
[http://dx.doi.org/10.24966/CBCM-1943/100004] 
[76] 
Cooper PD, Burt AM, Wilson JN. Critical effect of oxygen tension on rate of growth of animal cells in continuous suspended culture. Nature  1958; 182(4648): 1508-9.
[http://dx.doi.org/10.1038/1821508b0] [PMID: 13613312] 
[77] 
Antebi B, Rodriguez LA II, Walker KP III, et al. Short-term physiological hypoxia potentiates the therapeutic function of mesenchymal stem cells. Stem Cell Res Ther  2018; 9(1): 265.
[http://dx.doi.org/10.1186/s13287-018-1007-x] [PMID: 30305185] 
[78] 
Lee JH, Yoon YM, Lee SH. Hypoxic preconditioning promotes the bioactivities of mesenchymal stem cells via the HIF-1α-GRP78-Akt axis. Int J Mol Sci  2017; 18(6): 1320.
[http://dx.doi.org/10.3390/ijms18061320] 
[79] 
Bang OY, Jin KS, Hwang MN, et al. The effect of CXCR4 overexpression on mesenchymal stem cell transplantation in ischemic stroke. Cell Med  2012; 4(2): 65-76.
[http://dx.doi.org/10.3727/215517912X647172] [PMID: 26858855] 
[80] 
Haque N, Rahman MT, Abu Kasim NH, Alabsi AM, Alabsi AM. Hypoxic culture conditions as a solution for mesenchymal stem cell based regenerative therapy. ScientificWorldJournal  2013; 2013: 632972.
[http://dx.doi.org/10.1155/2013/632972] [PMID: 24068884] 
[81] 
Mulyani SWM, Ernawati DS, Astuti ER, Rantam FA. Hypoxic preconditioning effect on stromal cells derived factor-1 and C-X-C chemokine receptor type 4 expression in Wistar rat’s (Rattus norvegicus) bone marrow mesenchymal stem cells (in vitro study). Vet World  2018; 11(7): 965-70.
[http://dx.doi.org/10.14202/vetworld.2018.965-970] [PMID: 30147267] 
[82] 
Lu X, Han J, Xu X, et al. PGE2 promotes the migration of mesenchymal stem cells through the activation of FAK and ERK1/2 pathway. Stem Cells Int  2017; 20178178643
[http://dx.doi.org/10.1155/2017/8178643] [PMID: 28740516] 
[83] 
Wang JW, Qiu YR, Fu Y, Liu J, He ZJ, Huang ZT. Transplantation with hypoxia-preconditioned mesenchymal stem cells suppresses brain injury caused by cardiac arrest-induced global cerebral ischemia in rats. J Neurosci Res  2017; 95(10): 2059-70.
[http://dx.doi.org/10.1002/jnr.24025] [PMID: 28186348] 
[84] 
Lan YW, Choo KB, Chen CM, et al. Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis. Stem Cell Res Ther  2015; 6(1): 97.
[http://dx.doi.org/10.1186/s13287-015-0081-6] [PMID: 25986930] 
[85] 
Li B, Li C, Zhu M, et al. Hypoxia-induced mesenchymal stromal cells exhibit an enhanced therapeutic effect on radiation-induced lung injury in mice due to an increased proliferation potential and enhanced antioxidant ability. Cell Physiol Biochem  2017; 44(4): 1295-310.
[http://dx.doi.org/10.1159/000485490] [PMID: 29183009] 
[86] 
Putra A, Pertiwi D, Milla MN, et al. Hypoxia-preconditioned MSCs have superior effect in ameliorating renal function on acute renal failure animal model. Open Access Maced J Med Sci  2019; 7(3): 305-10.
[http://dx.doi.org/10.3889/oamjms.2019.049] [PMID: 30833992] 
[87] 
Sávio-Silva C, Soinski-Sousa PE, Balby-Rocha MT, Lira ÁD, Rangel ÉB. Mesenchymal stem cell therapy in acute kidney injury (AKI): review and perspectives. Rev Assoc Med Bras  1992; 66(Suppl 1): s45-54.
[88] 
Krampera M, Cosmi L, Angeli R, et al. Role for interferon-γ in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells  2006; 24(2): 386-98.
[http://dx.doi.org/10.1634/stemcells.2005-0008] [PMID: 16123384] 
[89] 
Jiang CM, Liu J, Zhao JY, et al. Effects of hypoxia on the immunomodulatory properties of human gingiva-derived mesenchymal stem cells. J Dent Res  2015; 94(1): 69-77.
[http://dx.doi.org/10.1177/0022034514557671] [PMID: 25403565] 
[90] 
Roemeling-van Rhijn M, Mensah FK, Korevaar SS, et al. Effects of hypoxia on the immunomodulatory properties of adipose tissue-derived mesenchymal stem cells. Front Immunol  2013; 4: 203.
[http://dx.doi.org/10.3389/fimmu.2013.00203] [PMID: 23882269] 
[91] 
Ishiuchi N, Nakashima A, Doi S, et al. Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats. Stem Cell Res Ther  2020; 11(1): 130.
[http://dx.doi.org/10.1186/s13287-020-01642-6] [PMID: 32197638] 
[92] 
Chen L, Xu Y, Zhao J, et al. Correction: Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. PLoS One  2015; 10(12): e0145565.
[http://dx.doi.org/10.1371/journal.pone.0145565] [PMID: 26683611] 
[93] 
Lee EY, Xia Y, Kim WS, et al. Hypoxia-enhanced wound-healing function of adipose-derived stem cells: Increase in stem cell proliferation and up-regulation of VEGF and bFGF. Wound Repair Regen  2009; 17(4): 540-7.
[http://dx.doi.org/10.1111/j.1524-475X.2009.00499.x] [PMID: 19614919] 
[94] 
Hu X, Xu Y, Zhong Z, et al. A large-scale investigation of hypoxia-preconditioned allogeneic mesenchymal stem cells for myocardial repair in nonhuman primates: Paracrine activity without remuscularization. Circ Res  2016; 118(6): 970-83.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.307516] [PMID: 26838793] 
[95] 
Zhilai Z, Biling M, Sujun Q, et al. Preconditioning in lowered oxygen enhances the therapeutic potential of human umbilical mesenchymal stem cells in a rat model of spinal cord injury. Brain Res  2016; 1642: 426-35.
[http://dx.doi.org/10.1016/j.brainres.2016.04.025] [PMID: 27085204] 
[96] 
Parekkadan B, Milwid JM. Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng  2010; 12: 87-117.
[http://dx.doi.org/10.1146/annurev-bioeng-070909-105309] [PMID: 20415588] 
[97] 
Zhao D, Liu L, Chen Q, et al. Hypoxia with Wharton’s jelly mesenchymal stem cell coculture maintains stemness of umbilical cord blood-derived CD34+ cells. Stem Cell Res Ther  2018; 9(1): 158.
[http://dx.doi.org/10.1186/s13287-018-0902-5] [PMID: 29895317] 
[98] 
Mohammadali F, Abroun S, Atashi A. Mild hypoxia and human bone marrow mesenchymal stem cells synergistically enhance expansion and homing capacity of human cord blood CD34+ stem cells. Iran J Basic Med Sci  2018; 21(7): 709-16.
[PMID: 30140410] 
[99] 
Kiani AA, Abdi J, Halabian R, et al. Over expression of HIF-1α in human mesenchymal stem cells increases their supportive functions for hematopoietic stem cells in an experimental co-culture model. Hematology  2014; 19(2): 85-98.
[http://dx.doi.org/10.1179/1607845413Y.0000000093] [PMID: 23710560] 
[100] 
Halvarsson C, Rörby E, Eliasson P, Lang S, Soneji S, Jönsson JI. Putative role of nuclear factor-kappa B but not hypoxia-inducible factor-1α in hypoxia-dependent regulation of oxidative stress in hematopoietic stem and progenitor cells. Antioxid Redox Signal  2019; 31(3): 211-26.
[http://dx.doi.org/10.1089/ars.2018.7551] [PMID: 30827134] 
[101] 
Salceda S, Caro J. Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem  1997; 272(36): 22642-7.
[http://dx.doi.org/10.1074/jbc.272.36.22642] [PMID: 9278421] 
[102] 
Menon A, Creo P, Piccoli M, et al. Chemical activation of the hypoxia-inducible factor reversibly reduces tendon stem cell proliferation, inhibits their differentiation, and maintains cell undifferentiation. Stem Cells Int  2018; 2018: 9468085.
[http://dx.doi.org/10.1155/2018/9468085] [PMID: 29713352] 
[103] 
Srinivasan S, Dunn JF. Stabilization of hypoxia-inducible factor-1α in buffer containing cobalt chloride for Western blot analysis. Anal Biochem  2011; 416(1): 120-2.
[http://dx.doi.org/10.1016/j.ab.2011.04.037] [PMID: 21601556] 
[104] 
Wu D, Yotnda P. Induction and testing of hypoxia in cell culture. J Vis Exp 2011; (54): e2899
[http://dx.doi.org/10.3791/2899] [PMID: 21860378] 
[105] 
McNeill LA, Hewitson KS, Gleadle JM, et al. The use of dioxygen by HIF prolyl hydroxylase (PHD1). Bioorg Med Chem Lett  2002; 12(12): 1547-50.
[http://dx.doi.org/10.1016/S0960-894X(02)00219-6] [PMID: 12039559] 
[106] 
Chun YS, Kim MS, Park JW. Oxygen-dependent and -independent regulation of HIF-1alpha. J Korean Med Sci  2002; 17(5): 581-8.
[http://dx.doi.org/10.3346/jkms.2002.17.5.581] [PMID: 12378005] 
[107] 
Yuan Y, Hilliard G, Ferguson T, Millhorn DE. Cobalt inhibits the interaction between hypoxia-inducible factor-α and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-α. J Biol Chem  2003; 278(18): 15911-6.
[http://dx.doi.org/10.1074/jbc.M300463200] [PMID: 12606543] 
[108] 
Pacary E, Legros H, Valable S, et al. Synergistic effects of CoCl(2) and ROCK inhibition on mesenchymal stem cell differentiation into neuron-like cells. J Cell Sci  2006; 119(Pt 13): 2667-78.
[http://dx.doi.org/10.1242/jcs.03004] [PMID: 16772336] 
[109] 
Yoo HI, Moon YH, Kim MS. Effects of CoCl2 on multi-lineage differentiation of C3H/10T1/2 mesenchymal stem cells. Korean J Physiol Pharmacol  2016; 20(1): 53-62.
[http://dx.doi.org/10.4196/kjpp.2016.20.1.53] [PMID: 26807023] 
[110] 
Araya J, Maruyama M, Inoue A, et al. Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages. Am J Physiol Lung Cell Mol Physiol  2002; 283(4): L849-58.
[http://dx.doi.org/10.1152/ajplung.00422.2001] [PMID: 12225962] 
[111] 
Dai ZJ, Gao J, Ma XB, et al. Up-regulation of hypoxia inducible factor-1α by cobalt chloride correlates with proliferation and apoptosis in PC-2 cells. J Exp Clin Cancer Res  2012; 31(1): 28.
[http://dx.doi.org/10.1186/1756-9966-31-28] [PMID: 22453051] 
[112] 
Salnikow K, An WG, Melillo G, Blagosklonny MV, Costa M. Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. Carcinogenesis  1999; 20(9): 1819-23.
[http://dx.doi.org/10.1093/carcin/20.9.1819] [PMID: 10469629] 
[113] 
Goldberg MA, Dunning SP, Bunn HF. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science  1988; 242(4884): 1412-5.
[http://dx.doi.org/10.1126/science.2849206] [PMID: 2849206] 
[114] 
Groenman FA, Rutter M, Wang J, Caniggia I, Tibboel D, Post M. Effect of chemical stabilizers of hypoxia-inducible factors on early lung development. Am J Physiol Lung Cell Mol Physiol  2007; 293(3): L557-67.
[http://dx.doi.org/10.1152/ajplung.00486.2006] [PMID: 17545484] 
[115] 
Liu XB, Wang JA, Ogle ME, Wei L. Prolyl hydroxylase inhibitor dimethyloxalylglycine enhances mesenchymal stem cell survival. J Cell Biochem  2009; 106(5): 903-11.
[http://dx.doi.org/10.1002/jcb.22064] [PMID: 19229863] 
[116] 
Peyvandi AA, Abbaszadeh HA, Roozbahany NA, et al. Deferoxamine promotes mesenchymal stem cell homing in noise-induced injured cochlea through PI3K/AKT pathway. Cell Prolif  2018; 51(2): e12434.
[http://dx.doi.org/10.1111/cpr.12434] [PMID: 29341316] 
[117] 
Sugrue T, Lowndes NF, Ceredig R. Hypoxia enhances the radioresistance of mouse mesenchymal stromal cells. Stem Cells  2014; 32(8): 2188-200.
[http://dx.doi.org/10.1002/stem.1683] [PMID: 24578291] 
[118] 
Ayrapetov MK, Xu C, Sun Y, et al. Activation of Hif1α by the prolylhydroxylase inhibitor dimethyoxalyglycine decreases radiosensitivity. PLoS One  2011; 6(10) e26064.
[http://dx.doi.org/10.1371/journal.pone.0026064] [PMID: 22016813] 
[119] 
Gupta N, Nizet V. Stabilization of hypoxia-inducible factor-1 alpha augments the therapeutic capacity of bone marrow-derived mesenchymal stem cells in experimental pneumonia. Front Med (Lausanne)  2018; 5: 131.
[http://dx.doi.org/10.3389/fmed.2018.00131] [PMID: 29780805] 
[120] 
Piret JP, Mottet D, Raes M, Michiels C. CoCl2, a chemical inducer of hypoxia-inducible factor-1, and hypoxia reduce apoptotic cell death in hepatoma cell line HepG2. Ann N Y Acad Sci  2002; 973(1): 443-7.
[http://dx.doi.org/10.1111/j.1749-6632.2002.tb04680.x] [PMID: 12485908] 
[121] 
Taheem DK, Foyt DA, Loaiza S, et al. Differential regulation of human bone marrow mesenchymal stromal cell chondrogenesis by hypoxia inducible factor-1α hydroxylase inhibitors. Stem Cells  2018; 36(9): 1380-92.
[http://dx.doi.org/10.1002/stem.2844] [PMID: 29726060] 
[122] 
Moirangthem RD, Singh S, Adsul A, Jalnapurkar S, Limaye L, Kale VP. Hypoxic niche-mediated regeneration of hematopoiesis in the engraftment window is dominantly affected by oxygen tension in the milieu. Stem Cells Dev  2015; 24(20): 2423-36.
[http://dx.doi.org/10.1089/scd.2015.0112] [PMID: 26107807] 
[123] 
Gupta P, Nath S, Meena RC, Kumar N. Comparative effects of hypoxia and hypoxia mimetic cobalt chloride on in vitro adhesion, biofilm formation and susceptibility to amphotericin B of Candida glabrata. J Mycol Med  2014; 24(4): e169-77.
[http://dx.doi.org/10.1016/j.mycmed.2014.08.003] [PMID: 25442919] 
[124] 
Zeng HL, Zhong Q, Qin YL, et al. Hypoxia-mimetic agents inhibit proliferation and alter the morphology of human umbilical cord-derived mesenchymal stem cells. BMC Cell Biol  2011; 12(1): 32.
[http://dx.doi.org/10.1186/1471-2121-12-32] [PMID: 21827650] 
[125] 
Lange C, Brunswig-Spickenheier B, Cappallo-Obermann H, et al. Radiation rescue: mesenchymal stromal cells protect from lethal irradiation. PLoS One  2011; 6(1): e14486.
[http://dx.doi.org/10.1371/journal.pone.0014486] [PMID: 21245929] 
[126] 
Eggenhofer E, Benseler V, Kroemer A, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol  2012; 3: 297.
[http://dx.doi.org/10.3389/fimmu.2012.00297] [PMID: 23056000] 
[127] 
Banfi A, Muraglia A, Dozin B, Mastrogiacomo M, Cancedda R, Quarto R. Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: Implications for their use in cell therapy. Exp Hematol  2000; 28(6): 707-15.
[http://dx.doi.org/10.1016/S0301-472X(00)00160-0] [PMID: 10880757] 
[128] 
Briquet A, Dubois S, Bekaert S, Dolhet M, Beguin Y, Gothot A. Prolonged ex vivo culture of human bone marrow mesenchymal stem cells influences their supportive activity toward NOD/SCID-repopulating cells and committed progenitor cells of B lymphoid and myeloid lineages. Haematologica  2010; 95(1): 47-56.
[http://dx.doi.org/10.3324/haematol.2009.008524] [PMID: 19713224] 
[129] 
Mastrolia I, Foppiani EM, Murgia A, et al. Challenges in clinical development of mesenchymal stromal/stem cells: concise review. Stem Cells Transl Med  2019; 8(11): 1135-48.
[http://dx.doi.org/10.1002/sctm.19-0044] [PMID: 31313507] 
[130] 
Hunter MP, Ismail N, Zhang X, et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One  2008; 3(11): e3694.
[http://dx.doi.org/10.1371/journal.pone.0003694] [PMID: 19002258] 
[131] 
Merchant ML, Rood IM, Deegens JKJ, Klein JB. Isolation and characterization of urinary extracellular vesicles: Implications for biomarker discovery. Nat Rev Nephrol  2017; 13(12): 731-49.
[http://dx.doi.org/10.1038/nrneph.2017.148] [PMID: 29081510] 
[132] 
Zonneveld MI, Brisson AR, van Herwijnen MJ, et al. Recovery of extracellular vesicles from human breast milk is influenced by sample collection and vesicle isolation procedures. J Extracell Vesicles  2014; 3(1): 24215.
[http://dx.doi.org/10.3402/jev.v3.24215] [PMID: 25206958] 
[133] 
Abreu SC, Weiss DJ, Rocco PR. Extracellular vesicles derived from mesenchymal stromal cells: A therapeutic option in respiratory diseases? Stem Cell Res Ther  2016; 7(1): 53.
[http://dx.doi.org/10.1186/s13287-016-0317-0] [PMID: 27075363] 
[134] 
Riazifar M, Pone EJ, Lötvall J, Zhao W. Stem cell extracellular vesicles: Extended messages of regeneration. Annu Rev Pharmacol Toxicol  2017; 57: 125-54.
[http://dx.doi.org/10.1146/annurev-pharmtox-061616-030146] [PMID: 27814025] 
[135] 
Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: Novel frontiers in regenerative medicine. Stem Cell Res Ther  2018; 9(1): 63.
[http://dx.doi.org/10.1186/s13287-018-0791-7] [PMID: 29523213] 
[136] 
Kalra H, Drummen GP, Mathivanan S. Focus on extracellular vesicles: Introducing the next small big thing. Int J Mol Sci  2016; 17(2): 170.
[http://dx.doi.org/10.3390/ijms17020170] [PMID: 26861301] 
[137] 
Ratajczak J, Miekus K, Kucia M, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: Evidence for horizontal transfer of mRNA and protein delivery. Leukemia  2006; 20(5): 847-56.
[http://dx.doi.org/10.1038/sj.leu.2404132] [PMID: 16453000] 
[138] 
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol  2007; 9(6): 654-9.
[http://dx.doi.org/10.1038/ncb1596] [PMID: 17486113] 
[139] 
Harrell CR, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Molecular mechanisms responsible for therapeutic potential of mesenchymal stem cell-derived secretome. Cells  2019; 8(5): 467.
[http://dx.doi.org/10.3390/cells8050467] [PMID: 31100966] 
[140] 
Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: Toward cell-free therapeutic applications. Mol Ther  2015; 23(5): 812-23.
[http://dx.doi.org/10.1038/mt.2015.44] [PMID: 25868399] 
[141] 
De Luca L, Trino S, Laurenzana I, et al. Mesenchymal stem cell derived extracellular vesicles: A role in hematopoietic transplantation? Int J Mol Sci  2017; 18(5): 1022.
[http://dx.doi.org/10.3390/ijms18051022] [PMID: 28486431] 
[142] 
Lonati C, Bassani GA, Brambilla D, et al. Mesenchymal stem cell-derived extracellular vesicles improve the molecular phenotype of isolated rat lungs during ischemia/reperfusion injury. J Heart Lung Transplant  2019; 38(12): 1306-16.
[http://dx.doi.org/10.1016/j.healun.2019.08.016] [PMID: 31530458] 
[143] 
Sisa C, Kholia S, Naylor J, et al. Mesenchymal stromal cell derived extracellular vesicles reduce hypoxia-ischaemia induced perinatal brain injury. Front Physiol  2019; 10: 282.
[http://dx.doi.org/10.3389/fphys.2019.00282] [PMID: 30941062] 
[144] 
Bollini S, Smits AM, Balbi C, Lazzarini E, Ameri P. Triggering endogenous cardiac repair and regeneration via extracellular vesicle-mediated communication. Front Physiol  2018; 9: 1497.
[http://dx.doi.org/10.3389/fphys.2018.01497] [PMID: 30405446] 
[145] 
Adamiak M, Cheng G, Bobis-Wozowicz S, et al. Induced pluripotent stem cell (iPSC)–derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs. Circ Res  2018; 122(2): 296-309.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311769] [PMID: 29118058] 
[146] 
Batsali AK, Georgopoulou A, Mavroudi I, Matheakakis A, Pontikoglou CG, Papadaki HA. The role of bone marrow mesenchymal stem cell derived extracellular vesicles (MSC-EVs) in normal and abnormal hematopoiesis and their therapeutic potential. J Clin Med  2020; 9(3): 856.
[http://dx.doi.org/10.3390/jcm9030856] [PMID: 32245055] 
[147] 
Tetta C, Deregibus MC, Camussi G. Stem cells and stem cell-derived extracellular vesicles in acute and chronic kidney diseases: mechanisms of repair. Ann Transl Med  2020; 8(8): 570.
[http://dx.doi.org/10.21037/atm.2020.03.19] [PMID: 32775371] 
[148] 
Schoefinius JS, Brunswig-Spickenheier B, Speiseder T, Krebs S, Just U, Lange C. Mesenchymal stromal cell-derived extracellular vesicles provide long-term survival after total body irradiation without additional hematopoietic stem cell support. Stem Cells  2017; 35(12): 2379-89.
[http://dx.doi.org/10.1002/stem.2716] [PMID: 29024236] 
[149] 
Bruno S, Grange C, Collino F, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One  2012; 7(3): e33115.
[http://dx.doi.org/10.1371/journal.pone.0033115] [PMID: 22431999] 
[150] 
Nakamura Y, Miyaki S, Ishitobi H, et al. Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett  2015; 589(11): 1257-65.
[http://dx.doi.org/10.1016/j.febslet.2015.03.031] [PMID: 25862500] 
[151] 
Kulkarni R, Bajaj M, Ghode S, Jalnapurkar S, Limaye L, Kale VP. Intercellular transfer of microvesicles from young mesenchymal stromal cells rejuvenates aged murine hematopoietic stem cells. Stem Cells  2018; 36(3): 420-33.
[http://dx.doi.org/10.1002/stem.2756] [PMID: 29230885] 
[152] 
Phan J, Kumar P, Hao D, Gao K, Farmer D, Wang A. Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy. J Extracell Vesicles  2018; 7(1): 1522236.
[http://dx.doi.org/10.1080/20013078.2018.1522236] [PMID: 30275938] 
[153] 
Sung DK, Chang YS, Sung SI, Ahn SY, Park WS. Thrombin preconditioning of extracellular vesicles derived from mesenchymal stem cells accelerates cutaneous wound healing by boosting their biogenesis and enriching cargo content. J Clin Med  2019; 8(4): 533.
[http://dx.doi.org/10.3390/jcm8040533] [PMID: 31003433] 
[154] 
Song Y, Dou H, Li X, et al. Exosomal miR-146a contributes to the enhanced therapeutic efficacy of interleukin-1β-primed mesenchymal stem cells against sepsis. Stem Cells  2017; 35(5): 1208-21.
[http://dx.doi.org/10.1002/stem.2564] [PMID: 28090688] 
[155] 
Harting MT, Srivastava AK, Zhaorigetu S, et al. Inflammation-stimulated mesenchymal stromal cell-derived extracellular vesicles attenuate inflammation. Stem Cells  2018; 36(1): 79-90.
[http://dx.doi.org/10.1002/stem.2730] [PMID: 29076623] 
[156] 
Zaborowski MP, Balaj L, Breakefield XO, Lai CP. Extracellular vesicles: Composition, biological relevance, and methods of study. Bioscience  2015; 65(8): 783-97.
[http://dx.doi.org/10.1093/biosci/biv084] [PMID: 26955082] 
[157] 
Zhang Q, Fu L, Liang Y, et al. Exosomes originating from MSCs stimulated with TGF-β and IFN-γ promote Treg differentiation. J Cell Physiol  2018; 233(9): 6832-40.
[http://dx.doi.org/10.1002/jcp.26436] [PMID: 29336475] 
[158] 
Sharma A, Rudra D. Emerging functions of regulatory T cells in tissue homeostasis. Front Immunol  2018; 9: 883.
[http://dx.doi.org/10.3389/fimmu.2018.00883] [PMID: 29887862] 
[159] 
Ti D, Hao H, Tong C, et al. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med  2015; 13(1): 308.
[http://dx.doi.org/10.1186/s12967-015-0642-6] [PMID: 26386558] 
[160] 
Martin-Rufino JD, Espinosa-Lara N, Osugui L, Sanchez-Guijo F. Targeting the immune system with mesenchymal stromal cell-derived extracellular vesicles: What is the cargo’s mechanism of action? Front Bioeng Biotechnol  2019; 7: 308.
[http://dx.doi.org/10.3389/fbioe.2019.00308] [PMID: 31781552] 
[161] 
Kehl D, Generali M, Mallone A, et al. Proteomic analysis of human mesenchymal stromal cell secretomes: A systematic comparison of the angiogenic potential. NPJ Regen Med  2019; 4(1): 8.
[http://dx.doi.org/10.1038/s41536-019-0070-y] [PMID: 31016031] 
[162] 
Almeria C, Weiss R, Roy M, et al. Hypoxia conditioned mesenchymal stem cell-derived extracellular vesicles induce increased vascular tube formation in vitro. Front Bioeng Biotechnol  2019; 7: 292.
[http://dx.doi.org/10.3389/fbioe.2019.00292] [PMID: 31709251] 
[163] 
Collino F, Lopes JA, Corrêa S, et al. Adipose-derived mesenchymal stromal cells under hypoxia: Changes in extracellular vesicles secretion and improvement of renal recovery after ischemic injury. Cell Physiol Biochem  2019; 52(6): 1463-83.
[PMID: 31099507] 
[164] 
Park H, Park H, Mun D, et al. Extracellular vesicles derived from hypoxic human mesenchymal stem cells attenuate GSK3β expression via miRNA-26a in an ischemia-reperfusion injury model. Yonsei Med J  2018; 59(6): 736-45.
[http://dx.doi.org/10.3349/ymj.2018.59.6.736] [PMID: 29978610] 
[165] 
Zhu J, Lu K, Zhang N, et al. Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif Cells Nanomed Biotechnol  2018; 46(8): 1659-70.
[PMID: 29141446] 
[166] 
Zhu LP, Tian T, Wang JY, et al. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics  2018; 8(22): 6163-77.
[http://dx.doi.org/10.7150/thno.28021] [PMID: 30613290] 
[167] 
Cui GH, Wu J, Mou FF, et al. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J  2018; 32(2): 654-68.
[http://dx.doi.org/10.1096/fj.201700600R] [PMID: 28970251] 
[168] 
An HY, Shin HS, Choi JS, Kim HJ, Lim JY, Kim YM. Adipose mesenchymal stem cell secretome modulated in hypoxia for remodeling of radiation-induced salivary gland damage. PLoS One  2015; 10(11): e0141862.
[http://dx.doi.org/10.1371/journal.pone.0141862] [PMID: 26529411] 
[169] 
Feng Y, Huang W, Wani M, Yu X, Ashraf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One  2014; 9(2): e88685.
[http://dx.doi.org/10.1371/journal.pone.0088685] [PMID: 24558412] 
[170] 
Budgude P, Kale V, Vaidya A. Mesenchymal stromal cell-derived extracellular vesicles as cell-free biologics for the ex vivo expansion of hematopoietic stem cells. Cell Biol Int  2020; 44(5): 1078-102.
[http://dx.doi.org/10.1002/cbin.11313] [PMID: 32009258] 
[171] 
Muscari C, Giordano E, Bonafè F, Govoni M, Pasini A, Guarnieri C. Priming adult stem cells by hypoxic pretreatments for applications in regenerative medicine. J Biomed Sci  2013; 20(1): 63.
[http://dx.doi.org/10.1186/1423-0127-20-63] [PMID: 23985033] 
[172] 
Park WS, Ahn SY, Sung SI, Ahn JY, Chang YS. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr Res  2018; 83(1-2): 214-22.
[http://dx.doi.org/10.1038/pr.2017.249] [PMID: 28972960] 
[173] 
Jalnapurkar S, Moirangthem RD, Singh S, Limaye L, Kale V. Microvesicles secreted by nitric oxide-primed mesenchymal stromal cells boost the engraftment potential of hematopoietic stem cells. Stem Cells  2019; 37(1): 128-38.
[http://dx.doi.org/10.1002/stem.2912] [PMID: 30290030] 
[174] 
Yu X, Lu C, Liu H, et al. Hypoxic preconditioning with cobalt of bone marrow mesenchymal stem cells improves cell migration and enhances therapy for treatment of ischemic acute kidney injury. PLoS One  2013; 8(5): e62703.
[http://dx.doi.org/10.1371/journal.pone.0062703] [PMID: 23671625] 
[175] 
Zhang M, Shi X, Wu J, et al. CoCl2 induced hypoxia enhances osteogenesis of rat bone marrow mesenchymal stem cells through cannabinoid receptor 2. Arch Oral Biol  2019; 108104525
[http://dx.doi.org/10.1016/j.archoralbio.2019.104525] [PMID: 31472278] 
Rights & Permissions Print Cite
Article Metrics
69
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1574888X15999200918110638	Print ISSN 1574-888X
Publisher Name Bentham Science Publisher	Online ISSN 2212-3946
Current Stem Cell Research & Therapy

Extracellular Vesicles Isolated from Mesenchymal Stromal Cells Primed with Hypoxia: Novel Strategy in Regenerative Medicine

Abstract

Related Journals

Related Books

Related Articles
