Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases

References

• Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685–1693. doi:10.1056/NEJMoa050333.
   PubMed Web of Science ®Google Scholar
• Silversides JA, Ferguson ND. Clinical review: acute respiratory distress syndrome - clinical ventilator management and adjunct therapy. Crit Care. 2013;17:225. doi:10.1186/cc12734.
   PubMed Web of Science ®Google Scholar
• The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–1308. doi:10.1056/NEJM200005043421801.
   PubMed Web of Science ®Google Scholar
• National Heart L, Blood Institute Acute Respiratory Distress Syndrome Clinical Trials N, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564–2575. doi:10.1056/NEJMoa062200.
   PubMed Web of Science ®Google Scholar
• Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–1116. doi:10.1056/NEJMoa1005372.
   PubMed Web of Science ®Google Scholar
• Hu SL, He HL, Pan C, et al. The effect of prone positioning on mortality in patients with acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. Crit Care. 2014;18:R109. doi:10.1186/cc13712.
   Google Scholar
• Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368:2159–2168. doi:10.1056/NEJMoa1214103.
   PubMed Web of Science ®Google Scholar
• Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349. doi:10.1056/NEJM200005043421806.
   PubMed Web of Science ®Google Scholar
• 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;8:315–317. doi:10.1080/14653240600855905.
   PubMed Web of Science ®Google Scholar
• Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res. 2014;15:39. doi:10.1186/1465-9921-15-39.
   PubMed Web of Science ®Google Scholar
• Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015;3:24–32. doi:10.1016/S2213-2600(14)70291-7.
   PubMed Web of Science ®Google Scholar
• Lee JW, Fang X, Krasnodembskaya A, et al. Concise review: Mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. Stem Cells. 2011;29:913–919. doi:10.1002/stem.643.
   PubMed Web of Science ®Google Scholar
• Guery BP, Mason CM, Dobard EP, et al. Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs. Am J Respir Crit Care Med. 1997;155:1777–1784. doi:10.1164/ajrccm.155.5.9154891.
   PubMed Web of Science ®Google Scholar
• Lee JW, Fang X, Gupta N, et al. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proceedings of the National Academy of Sciences of the United States of America 2009, 106:16357–16362. 10.1073/pnas.0907996106
   Google Scholar
• Lee JW, Krasnodembskaya A, McKenna DH, et al. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med. 2013;187:751–760. doi:10.1164/rccm.201206-0990OC.
   PubMed Web of Science ®Google Scholar
• Zhu YG, Feng XM, Abbott J, et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32:116–125. doi:10.1002/stem.1504.
   PubMed Web of Science ®Google Scholar
• Fang X, Neyrinck AP, Matthay MA, et al. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. J Biol Chem. 2010;285:26211–26222. doi:10.1074/jbc.M110.119917.
   PubMed Web of Science ®Google Scholar
• Gnecchi M, Zhang Z, Ni A, et al. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–1219. doi:10.1161/CIRCRESAHA.108.176826.
   PubMed Web of Science ®Google Scholar
• Phinney DG, Prockop DJ. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells. 2007;25:2896–2902. doi:10.1634/stemcells.2007-0637.
   PubMed Web of Science ®Google Scholar
• Tögel FE, Westenfelder C. Mesenchymal stem cells: a new therapeutic tool for AKI. Nat Rev Nephrol. 2010;6:179–183. doi:10.1038/nrneph.2009.229.
   PubMed Web of Science ®Google Scholar
• Wagers AJ, Sherwood RI, Christensen JL, et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science (New York, NY). 2002;297:2256–2259. doi:10.1126/science.1074807.
   Google Scholar
• Lange C, Tögel F, Ittrich H, et al. Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int. 2005;68:1613–1617. doi:10.1111/j.1523-1755.2005.00573.x.
   PubMed Web of Science ®Google Scholar
• Tögel F, Hu Z, Weiss K, et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289:F31–F42. doi:10.1152/ajprenal.00007.2005.
   PubMed Web of Science ®Google Scholar
• Fung ME, Thebaud B. Stem cell-based therapy for neonatal lung disease: it is in the juice. Pediatr Res. 2014;75:2–7. doi:10.1038/pr.2013.176.
   PubMed Web of Science ®Google Scholar
• Ionescu L, Byrne RN, Van Haaften T, et al. Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am J Physiol Lung Cell Mol Physiol. 2012;303:L967–L977. doi:10.1152/ajplung.00144.2011.
   PubMed Web of Science ®Google Scholar
• Jun D, Garat C, West J, et al. The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation. Stem Cells. 2011;29:725–735. doi:10.1002/stem.604.
   PubMed Web of Science ®Google Scholar
• Aslam M, Baveja R, Liang OD, et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med. 2009;180:1122–1130. doi:10.1164/rccm.200902-0242OC.
   PubMed Web of Science ®Google Scholar
• Van Haaften T, Byrne R, Bonnet S, et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med. 2009;180(1131–1142). doi:10.1164/rccm.200902-0179OC.
   PubMed Web of Science ®Google Scholar
• Hansmann G, Fernandez-Gonzalez A, Aslam M, et al. Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ. 2012;2:170–181. doi:10.4103/2045-8932.97603.
   PubMedGoogle Scholar
• Waszak P, Alphonse R, Vadivel A, et al. Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem Cells Dev. 2012;21:2789–2797. doi:10.1089/scd.2010.0566.
   PubMed Web of Science ®Google Scholar
• Tropea KA, Leder E, Aslam M, et al. Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2012;302:L829–L837. doi:10.1152/ajplung.00347.2011.
   PubMed Web of Science ®Google Scholar
• Sutsko RP, Young KC, Ribeiro A, et al. Long-term reparative effects of mesenchymal stem cell therapy following neonatal hyperoxia-induced lung injury. Pediatr Res. 2013;73:46–53. doi:10.1038/pr.2012.152.
   PubMed Web of Science ®Google Scholar
• Pierro M, Ionescu L, Montemurro T, et al. Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia. Thorax. 2013;68:475–484. doi:10.1136/thoraxjnl-2012-202323.
   PubMed Web of Science ®Google Scholar
• Ionescu LI, Alphonse RS, Arizmendi N, et al. Airway delivery of soluble factors from plastic-adherent bone marrow cells prevents murine asthma. Am J Respir Cell Mol Biol. 2012;46:207–216. doi:10.1165/rcmb.2010-0391OC.
   PubMed Web of Science ®Google Scholar
• Huh JW, Kim SY, Lee JH, et al. Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol. 2011;301:L255–L266. doi:10.1152/ajplung.00253.2010.
   PubMed Web of Science ®Google Scholar
• Kim SY, Lee JH, Kim HJ, et al. Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage. Am J Physiol Lung Cell Mol Physiol. 2012;302:L891–L908. doi:10.1152/ajplung.00288.2011.
   PubMed Web of Science ®Google Scholar
• McVey M, Tabuchi A, Kuebler WM. Microparticles and acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2012;303:L364–L381. doi:10.1152/ajplung.00354.2011.
   PubMed Web of Science ®Google Scholar
• Witwer KW, Buzas EI, Bemis LT, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013;2. doi:10.3402/jev.v2i0.20360.
   PubMedGoogle Scholar
• Gould SJ, Raposo G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles 2013;2. doi:10.3402/jev.v2i0.20389.
   PubMedGoogle Scholar
• Biancone L, Bruno S, Deregibus MC, et al. Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant. 2012;27:3037–3042. doi:10.1093/ndt/gfs168.
   PubMed Web of Science ®Google Scholar
• Dorronsoro A, Robbins PD. Regenerating the injured kidney with human umbilical cord mesenchymal stem cell-derived exosomes. Stem Cell Res Ther. 2013;4:39. doi:10.1186/scrt373.
   PubMed Web of Science ®Google Scholar
• Gyorgy B, Szabo TG, Pasztoi M, et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci. 2011;68:2667–2688. doi:10.1007/s00018-011-0689-3.
   PubMed Web of Science ®Google Scholar
• Simpson RJ, Jensen SS, Lim JW. Proteomic profiling of exosomes: current perspectives. Proteomics. 2008;8:4083–4099. doi:10.1002/pmic.200800109.
   PubMed Web of Science ®Google Scholar
• Mathivanan S, Ji H, Simpson RJ. Exosomes: extracellular organelles important in intercellular communication. J Proteomics. 2010;73:1907–1920. doi:10.1016/j.jprot.2010.06.006.
   PubMed Web of Science ®Google Scholar
• Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581–593. doi:10.1038/nri2567.
   PubMed Web of Science ®Google Scholar
• Zhang B, Yin Y, Lai RC, et al. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014;23:1233–1244. doi:10.1089/scd.2013.0479.
   PubMed Web of Science ®Google Scholar
• Mathivanan S, Simpson RJ. ExoCarta: A compendium of exosomal proteins and RNA. Proteomics. 2009;9:4997–5000. doi:10.1002/pmic.200900351.
   PubMed Web of Science ®Google Scholar
• Kalra H, Simpson RJ, Ji H, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012;10:e1001450. doi:10.1371/journal.pbio.1001453.
   PubMed Web of Science ®Google Scholar
• Camussi G, Deregibus MC, Bruno S, et al. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010;78:838–848. doi:10.1038/ki.2010.278.
   PubMed Web of Science ®Google Scholar
• Deregibus MC, Cantaluppi V, Calogero R, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 2007;110:2440–2448. doi:10.1182/blood-2007-03-078709.
   PubMed Web of Science ®Google Scholar
• 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;20:847–856. doi:10.1038/sj.leu.2404132.
   PubMed Web of Science ®Google Scholar
• Collino F, Deregibus MC, Bruno S, et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 2010;5:e11803. doi:10.1371/journal.pone.0011803.
   PubMed Web of Science ®Google Scholar
• Yuan A, Farber EL, Rapoport AL, et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One. 2009;4:e4722. doi:10.1371/journal.pone.0004722.
   PubMed Web of Science ®Google Scholar
• Kilpinen L, Impola U, Sankkila L, et al. Extracellular membrane vesicles from umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. J Extracell Vesicles. 2013;2. doi:10.3402/jev.v2i0.21927.
   PubMedGoogle Scholar
• Salomon C, Ryan J, Sobrevia L, et al. Exosomal signaling during hypoxia mediates microvascular endothelial cell migration and vasculogenesis. PLoS One. 2013;8:e68451. doi:10.1371/journal.pone.0068451.
   PubMed Web of Science ®Google Scholar
• Hayes M, Curley G, Ansari B, et al. Clinical review: stem cell therapies for acute lung injury/acute respiratory distress syndrome - hope or hype? Crit Care. 2012;16:205. doi:10.1186/cc10570.
   PubMed Web of Science ®Google Scholar
• Gotts JE, Matthay MA. Endogenous and exogenous cell-based pathways for recovery from acute respiratory distress syndrome. Clin Chest Med. 2014;35:797–809. doi:10.1016/j.ccm.2014.08.015.
   PubMed Web of Science ®Google Scholar
• Foronjy RF, Majka SM. The potential for resident lung mesenchymal stem cells to promote functional tissue regeneration: understanding microenvironmental cues. Cells. 2012;1:874. doi:10.3390/cells1040874.
   PubMedGoogle Scholar
• Lama VN, Smith L, Badri L, et al. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest. 2007;117:989–996. doi:10.1172/JCI29713.
   PubMed Web of Science ®Google Scholar
• Collins JJ, Thebaud B. Lung mesenchymal stromal cells in development and disease: to serve and protect? Antioxid Redox Signal. 2014;21:1849–1862. doi:10.1089/ars.2013.5781.
   PubMed Web of Science ®Google Scholar
• Zhang HC, Liu XB, Huang S, et al. Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells Dev. 2012;21:3289–3297. doi:10.1089/scd.2012.0095.
   PubMed Web of Science ®Google Scholar
• 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:e33115. doi:10.1371/journal.pone.0033115.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Xu H, Xu W, et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther. 2013;4:34. doi:10.1186/scrt373.
   PubMed Web of Science ®Google Scholar
• He J, Wang Y, Sun S, et al. Bone marrow stem cells-derived microvesicles protect against renal injury in the mouse remnant kidney model. Nephrology. 2012;17:493–500. doi:10.1111/j.1440-1797.2012.01589.x.
   PubMed Web of Science ®Google Scholar
• Reis LA, Borges FT, Simões MJ, et al. Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats. Plos One. 2012;7:e44092. doi:10.1371/journal.pone.0044092.
   PubMed Web of Science ®Google Scholar
• Bonventre JV. Microvesicles from mesenchymal stromal cells protect against acute kidney injury. J Am Soc Nephrol. 2009;20:927–928. doi:10.1681/ASN.2009030322.
   PubMed Web of Science ®Google Scholar
• Morigi M, Benigni A. Mesenchymal stem cells and kidney repair. Nephrol Dial Transplant. 2013;28:788–793. doi:10.1093/ndt/gfs556.
   PubMed Web of Science ®Google Scholar
• Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20:1053–1067. doi:10.1681/ASN.2008070798.
   PubMed Web of Science ®Google Scholar
• Zou X, Zhang G, Cheng Z, et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther. 2014;5:40. doi:10.1186/scrt428.
   PubMed Web of Science ®Google Scholar
• Grange C, Tapparo M, Bruno S, et al. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. Int J Mol Med. 2014;33:1055–1063. doi:10.3892/ijmm.2014.1663.
   PubMed Web of Science ®Google Scholar
• Sabin K, Kikyo N. Microvesicles as mediators of tissue regeneration. Transl Res. 2014;163:286–295. doi:10.1016/j.trsl.2013.10.005.
   PubMed Web of Science ®Google Scholar
• Tomasoni S, Longaretti L, Rota C, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev. 2013;22:772–780. doi:10.1089/scd.2012.0266.
   PubMed Web of Science ®Google Scholar
• Iglesias DM, El-Kares R, Taranta A, et al. Stem cell microvesicles transfer cystinosin to human cystinotic cells and reduce cystine accumulation in vitro. Plos One. 2012;7:e42840. doi:10.1371/journal.pone.0042840.
   PubMed Web of Science ®Google Scholar
• Bruno S, Camussi G. Role of mesenchymal stem cell-derived microvesicles in tissue repair. Pediatr Nephrol. 2013;28:2249–2254. doi:10.1007/s00467-013-2413-z.
   PubMed Web of Science ®Google Scholar
• Arslan F, Lai RC, Smeets MB, et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 2013;10:301–312. doi:10.1016/j.scr.2013.01.002.
   PubMed Web of Science ®Google Scholar
• Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4:214–222. doi:10.1016/j.scr.2009.12.003.
   PubMed Web of Science ®Google Scholar
• Lai RC, Arslan F, Tan SS, et al. Derivation and characterization of human fetal MSCs: an alternative cell source for large-scale production of cardioprotective microparticles. J Mol Cell Cardiol. 2010;48:1215–1224. doi:10.1016/j.yjmcc.2009.12.021.
   PubMed Web of Science ®Google Scholar
• Chen TS, Lai RC, Lee MM, et al. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 2010;38:215–224. doi:10.1093/nar/gkp857.
   PubMed Web of Science ®Google Scholar
• Bian S, Zhang L, Duan L, et al. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl). 2014;92:387–397. doi:10.1007/s00109-013-1110-5.
   PubMed Web of Science ®Google Scholar
• Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6:481–492. doi:10.2217/rme.11.35.
   PubMed Web of Science ®Google Scholar
• Kukielka GL, Hawkins HK, Michael L, et al. Regulation of intercellular adhesion molecule-1 (ICAM-1) in ischemic and reperfused canine myocardium. J Clin Invest. 1993;92:1504–1516. doi:10.1172/JCI116729.
   PubMed Web of Science ®Google Scholar
• Rieu S, Geminard C, Rabesandratana H, et al. Exosomes released during reticulocyte maturation bind to fibronectin via integrin alpha4beta1. Eur J Biochem. 2000;267:583–590.
   PubMedGoogle Scholar
• Hemler ME. Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Annu Rev Cell Dev Biol. 2003;19:397–422. doi:10.1146/annurev.cellbio.19.111301.153609.
   PubMed Web of Science ®Google Scholar
• Parolini I, Federici C, Raggi C, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009;284:34211–34222. doi:10.1074/jbc.M109.041152.
   PubMed Web of Science ®Google Scholar
• Schrader J. Mechanisms of ischemic injury in the heart. Basic Res Cardiol. 1985;80(Suppl 2):135–139.
   PubMed Web of Science ®Google Scholar
• Lai RC, Yeo RW, Tan KH, et al. Mesenchymal stem cell exosome ameliorates reperfusion injury through proteomic complementation. Regen Med. 2013;8:197–209. doi:10.2217/rme.13.4.
   PubMed Web of Science ®Google Scholar
• Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 2004;61:448–460. doi:10.1016/j.cardiores.2003.09.024.
   PubMed Web of Science ®Google Scholar
• Yellon DM, Baxter GF. Reperfusion injury revisited: is there a role for growth factor signaling in limiting lethal reperfusion injury? Trends Cardiovasc Med. 1999;9:245–249.
   PubMed Web of Science ®Google Scholar
• Hausenloy DJ, Yellon DM. Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail Rev. 2007;12:217–234. doi:10.1007/s10741-007-9026-1.
   PubMed Web of Science ®Google Scholar
• Lai RC, Tan SS, Teh BJ, et al. Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics. 2012;2012:971907. doi:10.1155/2012/971907.
   PubMedGoogle Scholar
• Clayton A, Harris CL, Court J, et al. Antigen-presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59. Eur J Immunol. 2003;33:522–531. doi:10.1002/immu.200310028.
   PubMed Web of Science ®Google Scholar
• Feng Y, Huang W, Wani M, et al. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One. 2014;9:e88685. doi:10.1371/journal.pone.0088685.
   PubMed Web of Science ®Google Scholar
• Yu B, Gong M, Wang Y, et al. Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles. PLoS One. 2013;8:e73304. doi:10.1371/journal.pone.0073304.
   Google Scholar
• Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013;22:845–854. doi:10.1089/scd.2012.0395.
   PubMed Web of Science ®Google Scholar
• Tan CY, Lai RC, Wong W, et al. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther. 2014;5:76. doi:10.1186/scrt465.
   PubMed Web of Science ®Google Scholar
• Yu YM, Gibbs KM, Davila J, et al. MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish. Eur J Neurosci. 2011;33:1587–1597. doi:10.1111/j.1460-9568.2011.07643.x.
   PubMed Web of Science ®Google Scholar
• Xin H, Li Y, Liu Z, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31:2737–2746. doi:10.1002/stem.1409.
   PubMed Web of Science ®Google Scholar
• Xin H, Li Y, Buller B, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30:1556–1564. doi:10.1002/stem.1129.
   PubMed Web of Science ®Google Scholar
• Xin H, Li Y, Cui Y, et al. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33:1711–1715. doi:10.1038/jcbfm.2013.152.
   PubMed Web of Science ®Google Scholar
• Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke. 1995;26:2135–2144.
   PubMed Web of Science ®Google Scholar
• Li Y, Chen J, Chopp M. Adult bone marrow transplantation after stroke in adult rats. Cell Transplantation. 2001;10:31–40.
   PubMed Web of Science ®Google Scholar
• Monsel A, Zhu YG, Gennai S, et al. Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med. 2015;192:324–336. doi:10.1164/rccm.201410-1765OC.
   PubMed Web of Science ®Google Scholar
• Phinney DG, Di Giuseppe M, Njah J, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. doi:10.1038/ncomms9472.
   PubMed Web of Science ®Google Scholar
• Gennai S, Monsel A, Hao Q, et al. Microvesicles derived from human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Transplant. 2015;15:2404–2412. doi:10.1111/ajt.13271.
   PubMed Web of Science ®Google Scholar
• Lee C, Mitsialis SA, Aslam M, et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation. 2012;126:2601–2611. doi:10.1161/CIRCULATIONAHA.112.114173.
   PubMed Web of Science ®Google Scholar
• Chen JY, An R, Liu ZJ, et al. Therapeutic effects of mesenchymal stem cell-derived microvesicles on pulmonary arterial hypertension in rats. Acta Pharmacol Sin. 2014;35:1121–1128. doi:10.1038/aps.2014.61.
   PubMed Web of Science ®Google Scholar
• Cruz FF, Borg ZD, Goodwin M, et al. Systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent mice. Stem Cells Transl Med. 2015 Nov;4(11):1302–1316. doi: 10.5966/sctm.2014-0280.
   PubMed Web of Science ®Google Scholar
• Schmidt EP, Yang Y, Janssen WJ, et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med. 2012;18:1217–1223. doi:10.1038/nm.2843.
   PubMed Web of Science ®Google Scholar
• Romieu-Mourez R, Francois M, Boivin MN, et al. Regulation of MHC class II expression and antigen processing in murine and human mesenchymal stromal cells by IFN-gamma, TGF-beta, and cell density. J Immunol. 2007;179:1549–1558.
   PubMed Web of Science ®Google Scholar
• Yeo RW, Lai RC, Zhang B, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65:336–341. doi:10.1016/j.addr.2012.07.001.
   PubMed Web of Science ®Google Scholar
• Chen TS, Arslan F, Yin Y, et al. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med. 2011;9:47. doi:10.1186/1479-5876-9-47.
   PubMed Web of Science ®Google Scholar
• Hupfeld J, Gorr IH, Schwald C, et al. Modulation of mesenchymal stromal cell characteristics by microcarrier culture in bioreactors. Biotechnol Bioeng. 2014;111:2290–2302. doi:10.1002/bit.25281.
   PubMed Web of Science ®Google Scholar
• Mitchell JP, Court J, Mason MD, et al. Increased exosome production from tumour cell cultures using the Integra CELLine Culture System. J Immunol Methods. 2008;335:98–105. doi:10.1016/j.jim.2008.03.001.
   PubMed Web of Science ®Google Scholar
• de Jong OG, Verhaar MC, Chen Y, et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles 2012;1. doi:10.3402/jev.v1i0.18396.
   PubMedGoogle Scholar
• Lara AR, Galindo E, Ramirez OT, et al. Living with heterogeneities in bioreactors: understanding the effects of environmental gradients on cells. Mol Biotechnol. 2006;34:355–381. doi:10.1385/MB:34:3:355.
   PubMed Web of Science ®Google Scholar
• King JA, Miller WM. Bioreactor development for stem cell expansion and controlled differentiation. Curr Opin Chem Biol. 2007;11:394–398. doi:10.1016/j.cbpa.2007.05.034.
   PubMed Web of Science ®Google Scholar
• Yeatts AB, Choquette DT, Fisher JP. Bioreactors to influence stem cell fate: augmentation of mesenchymal stem cell signaling pathways via dynamic culture systems. Biochim Biophys Acta. 2013;1830:2470–2480. doi:10.1016/j.bbagen.2012.06.007.
   PubMed Web of Science ®Google Scholar
• Waterman RS, Tomchuck SL, Henkle SL, et al. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One. 2010;5:e10088. doi:10.1371/journal.pone.0010088.
   PubMed Web of Science ®Google Scholar
• Cassatella MA, Mosna F, Micheletti A, et al. Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils. Stem Cells. 2011;29:1001–1011. doi:10.1002/stem.651.
   PubMed Web of Science ®Google Scholar
• Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol. 2012;12:383–396. doi:10.1038/nri3209.
   PubMed Web of Science ®Google Scholar
• van den Akker F, de Jager SC, Sluijter JP. Mesenchymal stem cell therapy for cardiac inflammation: immunomodulatory properties and the influence of toll-like receptors. Mediators Inflamm. 2013;2013:181020. doi:10.1155/2013/181020.
   PubMed Web of Science ®Google Scholar
• Gupta N, Su X, Popov B, et al. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol. 2007;179:1855–1863.
   PubMed Web of Science ®Google Scholar
• Xu J, Qu J, Cao L, et al. Mesenchymal stem cell-based angiopoietin-1 gene therapy for acute lung injury induced by lipopolysaccharide in mice. J Pathol. 2008;214:472–481. doi:10.1002/path.2302.
   PubMed Web of Science ®Google Scholar
• Mei SH, McCarter SD, Deng Y, et al. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med. 2007;4:e269. doi:10.1371/journal.pmed.0040269.
   PubMed Web of Science ®Google Scholar
• Gupta N, Krasnodembskaya A, Kapetanaki M, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax. 2012;67:533–539. doi:10.1136/thoraxjnl-2011-201176.
   PubMed Web of Science ®Google Scholar
• Krasnodembskaya A, Song Y, Fang X, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010;28:2229–2238. doi:10.1002/stem.544.
   PubMed Web of Science ®Google Scholar
• Nemeth K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42–49. doi:10.1038/nm.1905.
   PubMed Web of Science ®Google Scholar
• Gonzalez-Rey E, Anderson P, González MA, et al. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut. 2009;58:929–939. doi:10.1136/gut.2008.168534.
   PubMed Web of Science ®Google Scholar
• Mei SH, Haitsma JJ, Dos Santos CC, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182:1047–1057. doi:10.1164/rccm.201001-0010OC.
   PubMed Web of Science ®Google Scholar
• Rani S, Ryan AE, Griffin MD, et al. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther. 2015;23:812–823. doi:10.1038/mt.2015.44.
   PubMed Web of Science ®Google Scholar
• Roccaro AM, Sacco A, Maiso P, et al. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest. 2013;123:1542–1555. doi:10.1172/JCI66517.
   PubMed Web of Science ®Google Scholar
• Roccaro AM, Sacco A, Thompson B, et al. MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood. 2009;113:6669–6680. doi:10.1182/blood-2009-01-198408.
   PubMed Web of Science ®Google Scholar
• Zhu W, Huang L, Li Y, et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett. 2012;315:28–37. doi:10.1016/j.canlet.2011.10.002.
   PubMed Web of Science ®Google Scholar
• Lee JK, Park SR, Jung BK, et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One. 2013;8:e84256. doi:10.1371/journal.pone.0084256.
   PubMed Web of Science ®Google Scholar