{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:01:54Z","timestamp":1790434914497,"version":"4.1.0"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,10,24]],"date-time":"2018-10-24T00:00:00Z","timestamp":1540339200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,10,24]],"date-time":"2018-10-24T00:00:00Z","timestamp":1540339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"START-Program of the Faculty of Medicine RWTH Aachen"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cardiovascular diseases are the main cause of death worldwide, demanding new treatments and interventions. Recently, extracellular vesicles (EVs) came in focus as important carriers of protective molecules such as miRNAs and proteins which might contribute to e.g. improved cardiac function after myocardial infarction. EVs can be secreted from almost every cell type in the human body and can be transferred via the bloodstream in almost every compartment. To provide an all-encompassing overview of studies investigating these beneficial properties of EVs we performed a systematic review\/meta-analysis of studies investigating the cardioprotective characteristics of EVs. Forty-three studies were investigated and catalogued according to the EV source. We provide an in-depth analysis of the purification method, size of the EVs, the conducted experiments to investigate the beneficial properties of EVs as well as the major effector molecule encapsulated in EVs mediating protection. This study provides evidence that EVs from different cell types and body fluids provide cardioprotection in different <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> studies. A meta-analysis was performed to estimate the underlying effect size. In conclusion, we demonstrated that EVs from different sources might serve as a promising tool for treating cardiovascular diseases in the future.<\/jats:p>","DOI":"10.1038\/s41598-018-33862-5","type":"journal-article","created":{"date-parts":[[2018,10,18]],"date-time":"2018-10-18T10:18:32Z","timestamp":1539857912000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Evaluation of the cardioprotective potential of extracellular vesicles \u2013 a systematic review and meta-analysis"],"prefix":"10.1038","volume":"8","author":[{"given":"Sebastian","family":"Wendt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Goetzenich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Goettsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Stoppe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Bleilevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Kraemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Benstoem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,10,24]]},"reference":[{"key":"33862_CR1","unstructured":"World Health Organization. Cardiovascular diseases (CVDs), http:\/\/www.who.int\/news-room\/fact-sheets\/detail\/cardiovascular-diseases-(cvds) (2017)."},{"key":"33862_CR2","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1177\/1089253211436350","volume":"16","author":"A Frank","year":"2012","unstructured":"Frank, A. et al. Myocardial ischemia reperfusion injury: from basic science to clinical bedside. Semin Cardiothorac Vasc Anesth 16, 123\u2013132, https:\/\/doi.org\/10.1177\/1089253211436350 (2012).","journal-title":"Semin Cardiothorac Vasc Anesth"},{"key":"33862_CR3","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/s00392-011-0397-x","volume":"101","author":"DJ Hausenloy","year":"2012","unstructured":"Hausenloy, D. J. et al. Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery (ERICCA): rationale and study design of a multi-centre randomized double-blinded controlled clinical trial. Clin Res Cardiol 101, 339\u2013348, https:\/\/doi.org\/10.1007\/s00392-011-0397-x (2012).","journal-title":"Clin Res Cardiol"},{"key":"33862_CR4","doi-asserted-by":"publisher","first-page":"e92827","DOI":"10.1371\/journal.pone.0092827","volume":"9","author":"A Goetzenich","year":"2014","unstructured":"Goetzenich, A. et al. The role of macrophage migration inhibitory factor in anesthetic-induced myocardial preconditioning. Plos One 9, e92827, https:\/\/doi.org\/10.1371\/journal.pone.0092827 (2014).","journal-title":"Plos One"},{"key":"33862_CR5","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1093\/icvts\/ivt450","volume":"18","author":"A Goetzenich","year":"2014","unstructured":"Goetzenich, A. et al. The role of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in late-phase preconditioning with xenon, isoflurane and levosimendan in rat cardiomyocytes. Interact Cardiovasc Thorac Surg 18, 321\u2013328, https:\/\/doi.org\/10.1093\/icvts\/ivt450 (2014).","journal-title":"Interact Cardiovasc Thorac Surg"},{"key":"33862_CR6","doi-asserted-by":"publisher","first-page":"2667","DOI":"10.1007\/s00018-011-0689-3","volume":"68","author":"B Gyorgy","year":"2011","unstructured":"Gyorgy, B. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68, 2667\u20132688, https:\/\/doi.org\/10.1007\/s00018-011-0689-3 (2011).","journal-title":"Cell Mol Life Sci"},{"key":"33862_CR7","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1016\/j.jacc.2015.02.026","volume":"65","author":"JM Vicencio","year":"2015","unstructured":"Vicencio, J. M. et al. Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J Am Coll Cardiol 65, 1525\u20131536, https:\/\/doi.org\/10.1016\/j.jacc.2015.02.026 (2015).","journal-title":"J Am Coll Cardiol"},{"key":"33862_CR8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.yjmcc.2014.01.004","volume":"68","author":"Z Giricz","year":"2014","unstructured":"Giricz, Z. et al. Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. J Mol Cell Cardiol 68, 75\u201378, https:\/\/doi.org\/10.1016\/j.yjmcc.2014.01.004 (2014).","journal-title":"J Mol Cell Cardiol"},{"key":"33862_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/srep13721","volume":"5","author":"X Wang","year":"2015","unstructured":"Wang, X. et al. Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis. Sci Rep 5, 13721, https:\/\/doi.org\/10.1038\/srep13721 (2015).","journal-title":"Sci Rep"},{"key":"33862_CR10","doi-asserted-by":"publisher","first-page":"e88685","DOI":"10.1371\/journal.pone.0088685","volume":"9","author":"Y Feng","year":"2014","unstructured":"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 9, e88685, https:\/\/doi.org\/10.1371\/journal.pone.0088685 (2014).","journal-title":"Plos One"},{"key":"33862_CR11","doi-asserted-by":"publisher","first-page":"26913","DOI":"10.3402\/jev.v3.26913","volume":"3","author":"J Lotvall","year":"2014","unstructured":"Lotvall, J. et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3, 26913, https:\/\/doi.org\/10.3402\/jev.v3.26913 (2014).","journal-title":"J Extracell Vesicles"},{"key":"33862_CR12","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1038\/nmeth.4185","volume":"14","author":"E-T Consortium","year":"2017","unstructured":"Consortium, E.-T. et al. EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research. Nat Methods 14, 228\u2013232, https:\/\/doi.org\/10.1038\/nmeth.4185 (2017).","journal-title":"Nat Methods"},{"key":"33862_CR13","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1093\/cvr\/cvu167","volume":"103","author":"L Barile","year":"2014","unstructured":"Barile, L. et al. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res 103, 530\u2013541, https:\/\/doi.org\/10.1093\/cvr\/cvu167 (2014).","journal-title":"Cardiovasc Res"},{"key":"33862_CR14","doi-asserted-by":"publisher","first-page":"440","DOI":"10.5966\/sctm.2015-0177","volume":"5","author":"T Kang","year":"2016","unstructured":"Kang, T. et al. Adipose-Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA-31. Stem cells translational medicine 5, 440\u2013450, https:\/\/doi.org\/10.5966\/sctm.2015-0177 (2016).","journal-title":"Stem cells translational medicine"},{"key":"33862_CR15","first-page":"10832","volume":"8","author":"F Ma","year":"2015","unstructured":"Ma, F., Liu, H., Shen, Y., Zhang, Y. & Pan, S. Platelet-derived microvesicles are involved in cardio-protective effects of remote preconditioning. International journal of clinical and experimental pathology 8, 10832\u201310839 (2015).","journal-title":"International journal of clinical and experimental pathology"},{"key":"33862_CR16","doi-asserted-by":"publisher","first-page":"e0159105","DOI":"10.1371\/journal.pone.0159105","volume":"11","author":"K Svennerholm","year":"2016","unstructured":"Svennerholm, K. et al. DNA Content in Extracellular Vesicles Isolated from Porcine Coronary Venous Blood Directly after Myocardial Ischemic Preconditioning. Plos One 11, e0159105, https:\/\/doi.org\/10.1371\/journal.pone.0159105 (2016).","journal-title":"Plos One"},{"key":"33862_CR17","doi-asserted-by":"publisher","first-page":"2136","DOI":"10.1172\/JCI70577","volume":"124","author":"C Bang","year":"2014","unstructured":"Bang, C. et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest 124, 2136\u20132146, https:\/\/doi.org\/10.1172\/JCI70577 (2014).","journal-title":"J Clin Invest"},{"key":"33862_CR18","doi-asserted-by":"publisher","first-page":"2628","DOI":"10.1074\/mcp.M115.055731","volume":"15","author":"ES Cheow","year":"2016","unstructured":"Cheow, E. S. et al. Plasma-derived Extracellular Vesicles Contain Predictive Biomarkers and Potential Therapeutic Targets for Myocardial Ischemic (MI) Injury. Molecular & cellular proteomics: MCP 15, 2628\u20132640, https:\/\/doi.org\/10.1074\/mcp.M115.055731 (2016).","journal-title":"Molecular & cellular proteomics: MCP"},{"key":"33862_CR19","doi-asserted-by":"publisher","first-page":"e85396","DOI":"10.1371\/journal.pone.0085396","volume":"9","author":"S Gu","year":"2014","unstructured":"Gu, S. et al. EPC-derived microvesicles protect cardiomyocytes from Ang II-induced hypertrophy and apoptosis. Plos One 9, e85396, https:\/\/doi.org\/10.1371\/journal.pone.0085396 (2014).","journal-title":"Plos One"},{"key":"33862_CR20","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.scr.2009.12.003","volume":"4","author":"RC Lai","year":"2010","unstructured":"Lai, R. C. et al. Exosome secreted by MSC reduces myocardial ischemia\/reperfusion injury. Stem Cell Res 4, 214\u2013222, https:\/\/doi.org\/10.1016\/j.scr.2009.12.003 (2010).","journal-title":"Stem Cell Res"},{"key":"33862_CR21","doi-asserted-by":"publisher","first-page":"e0138849","DOI":"10.1371\/journal.pone.0138849","volume":"10","author":"NA Garcia","year":"2015","unstructured":"Garcia, N. A., Ontoria-Oviedo, I., Gonzalez-King, H., Diez-Juan, A. & Sepulveda, P. Glucose Starvation in Cardiomyocytes Enhances Exosome Secretion and Promotes Angiogenesis in Endothelial Cells. Plos One 10, e0138849, https:\/\/doi.org\/10.1371\/journal.pone.0138849 (2015).","journal-title":"Plos One"},{"key":"33862_CR22","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1161\/CIRCRESAHA.116.304360","volume":"116","author":"WD Gray","year":"2015","unstructured":"Gray, W. D. et al. Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ Res 116, 255\u2013263, https:\/\/doi.org\/10.1161\/CIRCRESAHA.116.304360 (2015).","journal-title":"Circ Res"},{"key":"33862_CR23","doi-asserted-by":"publisher","first-page":"761643","DOI":"10.1155\/2015\/761643","volume":"2015","author":"Y Zhao","year":"2015","unstructured":"Zhao, Y. et al. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury. Stem Cells Int 2015, 761643, https:\/\/doi.org\/10.1155\/2015\/761643 (2015).","journal-title":"Stem Cells Int"},{"key":"33862_CR24","doi-asserted-by":"publisher","first-page":"3111","DOI":"10.2337\/db15-1563","volume":"65","author":"X Wang","year":"2016","unstructured":"Wang, X. et al. Hsp20-Mediated Activation of Exosome Biogenesis in Cardiomyocytes Improves Cardiac Function and Angiogenesis in Diabetic Mice. Diabetes 65, 3111\u20133128, https:\/\/doi.org\/10.2337\/db15-1563 (2016).","journal-title":"Diabetes"},{"key":"33862_CR25","first-page":"377","volume":"17","author":"H Namazi","year":"2018","unstructured":"Namazi, H. et al. Exosomes Secreted by Normoxic and Hypoxic Cardiosphere-derived Cells Have Anti-apoptotic Effect. Iran J Pharm Res 17, 377\u2013385 (2018).","journal-title":"Iran J Pharm Res"},{"key":"33862_CR26","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1002\/sctm.16-0297","volume":"6","author":"C Balbi","year":"2017","unstructured":"Balbi, C. et al. First Characterization of Human Amniotic Fluid Stem Cell Extracellular Vesicles as a Powerful Paracrine Tool Endowed with Regenerative Potential. Stem cells translational medicine 6, 1340\u20131355, https:\/\/doi.org\/10.1002\/sctm.16-0297 (2017).","journal-title":"Stem cells translational medicine"},{"key":"33862_CR27","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1111\/jcmm.13302","volume":"22","author":"SM Davidson","year":"2018","unstructured":"Davidson, S. M. et al. Cardioprotection mediated by exosomes is impaired in the setting of type II diabetes but can be rescued by the use of non-diabetic exosomes in vitro. J Cell Mol Med 22, 141\u2013151, https:\/\/doi.org\/10.1111\/jcmm.13302 (2018).","journal-title":"J Cell Mol Med"},{"key":"33862_CR28","doi-asserted-by":"publisher","first-page":"4150","DOI":"10.1002\/jcb.26621","volume":"119","author":"H Namazi","year":"2018","unstructured":"Namazi, H. et al. Exosomes secreted by hypoxic cardiosphere-derived cells enhance tube formation and increase pro-angiogenic miRNA. J Cell Biochem 119, 4150\u20134160, https:\/\/doi.org\/10.1002\/jcb.26621 (2018).","journal-title":"J Cell Biochem"},{"key":"33862_CR29","doi-asserted-by":"publisher","unstructured":"Obata, Y. et al. Adiponectin\/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release. JCI Insight 3, https:\/\/doi.org\/10.1172\/jci.insight.99680 (2018).","DOI":"10.1172\/jci.insight.99680"},{"key":"33862_CR30","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1093\/cvr\/cvx118","volume":"113","author":"TM Ribeiro-Rodrigues","year":"2017","unstructured":"Ribeiro-Rodrigues, T. M. et al. Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis. Cardiovasc Res 113, 1338\u20131350, https:\/\/doi.org\/10.1093\/cvr\/cvx118 (2017).","journal-title":"Cardiovasc Res"},{"key":"33862_CR31","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.ijcha.2015.05.006","volume":"8","author":"K Svennerholm","year":"2015","unstructured":"Svennerholm, K. et al. Myocardial ischemic preconditioning in a porcine model leads to rapid changes in cardiac extracellular vesicle messenger RNA content. Int J Cardiol Heart Vasc 8, 62\u201367, https:\/\/doi.org\/10.1016\/j.ijcha.2015.05.006 (2015).","journal-title":"Int J Cardiol Heart Vasc"},{"key":"33862_CR32","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-018-0674-1","volume":"113","author":"J Wider","year":"2018","unstructured":"Wider, J. et al. Remote ischemic preconditioning fails to reduce infarct size in the Zucker fatty rat model of type-2 diabetes: role of defective humoral communication. Basic research in cardiology 113, 16, https:\/\/doi.org\/10.1007\/s00395-018-0674-1 (2018).","journal-title":"Basic research in cardiology"},{"key":"33862_CR33","doi-asserted-by":"publisher","first-page":"1390391","DOI":"10.1080\/20013078.2017.1390391","volume":"6","author":"S Borosch","year":"2017","unstructured":"Borosch, S. et al. Characterization of extracellular vesicles derived from cardiac cells in an in vitro model of preconditioning. J Extracell Vesicles 6, 1390391, https:\/\/doi.org\/10.1080\/20013078.2017.1390391 (2017).","journal-title":"J Extracell Vesicles"},{"key":"33862_CR34","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.bbrc.2013.01.015","volume":"431","author":"L Chen","year":"2013","unstructured":"Chen, L. et al. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia\/reperfusion injury. Biochem Biophys Res Commun 431, 566\u2013571, https:\/\/doi.org\/10.1016\/j.bbrc.2013.01.015 (2013).","journal-title":"Biochem Biophys Res Commun"},{"key":"33862_CR35","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/j.stemcr.2014.04.006","volume":"2","author":"AG Ibrahim","year":"2014","unstructured":"Ibrahim, A. G., Cheng, K. & Marban, E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports 2, 606\u2013619, https:\/\/doi.org\/10.1016\/j.stemcr.2014.04.006 (2014).","journal-title":"Stem Cell Reports"},{"key":"33862_CR36","doi-asserted-by":"publisher","first-page":"659890","DOI":"10.1155\/2015\/659890","volume":"2015","author":"K Kang","year":"2015","unstructured":"Kang, K. et al. Exosomes Secreted from CXCR4 Overexpressing Mesenchymal Stem Cells Promote Cardioprotection via Akt Signaling Pathway following Myocardial Infarction. Stem Cells Int 2015, 659890, https:\/\/doi.org\/10.1155\/2015\/659890 (2015).","journal-title":"Stem Cells Int"},{"key":"33862_CR37","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-014-0423-z","volume":"109","author":"J Li","year":"2014","unstructured":"Li, J. et al. MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Basic research in cardiology 109, 423, https:\/\/doi.org\/10.1007\/s00395-014-0423-z (2014).","journal-title":"Basic research in cardiology"},{"key":"33862_CR38","doi-asserted-by":"publisher","first-page":"S60","DOI":"10.1161\/CIRCULATIONAHA.113.007917","volume":"130","author":"SG Ong","year":"2014","unstructured":"Ong, S. G. et al. Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer. Circulation 130, S60\u201369, https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.113.007917 (2014).","journal-title":"Circulation"},{"key":"33862_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.181","volume":"7","author":"J Xiao","year":"2016","unstructured":"Xiao, J. et al. Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4. Cell Death Dis 7, e2277, https:\/\/doi.org\/10.1038\/cddis.2016.181 (2016).","journal-title":"Cell Death Dis"},{"key":"33862_CR40","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.ijcard.2014.10.144","volume":"178","author":"T Yamaguchi","year":"2015","unstructured":"Yamaguchi, T. et al. Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction. Int J Cardiol 178, 239\u2013246, https:\/\/doi.org\/10.1016\/j.ijcard.2014.10.144 (2015).","journal-title":"Int J Cardiol"},{"key":"33862_CR41","doi-asserted-by":"publisher","first-page":"e73304","DOI":"10.1371\/journal.pone.0073304","volume":"8","author":"B Yu","year":"2013","unstructured":"Yu, B. et al. Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles. Plos One 8, e73304, https:\/\/doi.org\/10.1371\/journal.pone.0073304 (2013).","journal-title":"Plos One"},{"key":"33862_CR42","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.ijcard.2014.12.043","volume":"182","author":"B Yu","year":"2015","unstructured":"Yu, B. et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol 182, 349\u2013360, https:\/\/doi.org\/10.1016\/j.ijcard.2014.12.043 (2015).","journal-title":"Int J Cardiol"},{"key":"33862_CR43","doi-asserted-by":"publisher","first-page":"e32765","DOI":"10.1371\/journal.pone.0032765","volume":"7","author":"X Zhang","year":"2012","unstructured":"Zhang, X. et al. Hsp20 functions as a novel cardiokine in promoting angiogenesis via activation of VEGFR2. Plos One 7, e32765, https:\/\/doi.org\/10.1371\/journal.pone.0032765 (2012).","journal-title":"Plos One"},{"key":"33862_CR44","doi-asserted-by":"publisher","first-page":"2415","DOI":"10.1159\/000438594","volume":"37","author":"X Teng","year":"2015","unstructured":"Teng, X. et al. Mesenchymal Stem Cell-Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti-Inflammation. Cell Physiol Biochem 37, 2415\u20132424, https:\/\/doi.org\/10.1159\/000438594 (2015).","journal-title":"Cell Physiol Biochem"},{"key":"33862_CR45","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.ijcard.2015.05.020","volume":"192","author":"Y Wang","year":"2015","unstructured":"Wang, Y. et al. Exosomes\/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 192, 61\u201369, https:\/\/doi.org\/10.1016\/j.ijcard.2015.05.020 (2015).","journal-title":"Int J Cardiol"},{"key":"33862_CR46","doi-asserted-by":"publisher","unstructured":"Zhang, Z. et al. Pretreatment of Cardiac Stem Cells With Exosomes Derived From Mesenchymal Stem Cells Enhances Myocardial Repair. J Am Heart Assoc 5, https:\/\/doi.org\/10.1161\/JAHA.115.002856 (2016).","DOI":"10.1161\/JAHA.115.002856"},{"key":"33862_CR47","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1161\/CIRCULATIONAHA.116.024590","volume":"136","author":"G de Couto","year":"2017","unstructured":"de Couto, G. et al. Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning. Circulation 136, 200\u2013214, https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.116.024590 (2017).","journal-title":"Circulation"},{"key":"33862_CR48","doi-asserted-by":"publisher","first-page":"e0191616","DOI":"10.1371\/journal.pone.0191616","volume":"13","author":"B Shi","year":"2018","unstructured":"Shi, B. et al. Bone marrow mesenchymal stem cell-derived exosomal miR-21 protects C-kit + cardiac stem cells from oxidative injury through the PTEN\/PI3K\/Akt axis. Plos One 13, e0191616, https:\/\/doi.org\/10.1371\/journal.pone.0191616 (2018).","journal-title":"Plos One"},{"key":"33862_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0274-x","volume":"9","author":"W Minghua","year":"2018","unstructured":"Minghua, W. et al. Plasma exosomes induced by remote ischaemic preconditioning attenuate myocardial ischaemia\/reperfusion injury by transferring miR-24. Cell Death Dis 9, 320, https:\/\/doi.org\/10.1038\/s41419-018-0274-x (2018).","journal-title":"Cell Death Dis"},{"key":"33862_CR50","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.scr.2013.01.002","volume":"10","author":"F Arslan","year":"2013","unstructured":"Arslan, F. 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 10, 301\u2013312, https:\/\/doi.org\/10.1016\/j.scr.2013.01.002 (2013).","journal-title":"Stem Cell Res"},{"key":"33862_CR51","doi-asserted-by":"publisher","first-page":"960926","DOI":"10.1155\/2015\/960926","volume":"2015","author":"AC Vandergriff","year":"2015","unstructured":"Vandergriff, A. C. et al. Intravenous Cardiac Stem Cell-Derived Exosomes Ameliorate Cardiac Dysfunction in Doxorubicin Induced Dilated Cardiomyopathy. Stem Cells Int 2015, 960926, https:\/\/doi.org\/10.1155\/2015\/960926 (2015).","journal-title":"Stem Cells Int"},{"key":"33862_CR52","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1161\/CIRCRESAHA.116.308139","volume":"118","author":"P Zhou","year":"2016","unstructured":"Zhou, P. & Pu, W. T. Recounting Cardiac Cellular Composition. Circ Res 118, 368\u2013370, https:\/\/doi.org\/10.1161\/CIRCRESAHA.116.308139 (2016).","journal-title":"Circ Res"},{"key":"33862_CR53","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1038\/nm1618","volume":"13","author":"PC Hsieh","year":"2007","unstructured":"Hsieh, P. C. et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13, 970\u2013974, https:\/\/doi.org\/10.1038\/nm1618 (2007).","journal-title":"Nat Med"},{"key":"33862_CR54","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/nature11682","volume":"493","author":"SE Senyo","year":"2013","unstructured":"Senyo, S. E. et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493, 433\u2013436, https:\/\/doi.org\/10.1038\/nature11682 (2013).","journal-title":"Nature"},{"key":"33862_CR55","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1161\/CIRCULATIONAHA.106.655209","volume":"115","author":"RR Smith","year":"2007","unstructured":"Smith, R. R. et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896\u2013908, https:\/\/doi.org\/10.1161\/CIRCULATIONAHA.106.655209 (2007).","journal-title":"Circulation"},{"key":"33862_CR56","doi-asserted-by":"publisher","first-page":"1378056","DOI":"10.1080\/20013078.2017.1378056","volume":"6","author":"K Menck","year":"2017","unstructured":"Menck, K. et al. Neutral sphingomyelinases control extracellular vesicles budding from the plasma membrane. J Extracell Vesicles 6, 1378056, https:\/\/doi.org\/10.1080\/20013078.2017.1378056 (2017).","journal-title":"J Extracell Vesicles"},{"key":"33862_CR57","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1126\/science.1153124","volume":"319","author":"K Trajkovic","year":"2008","unstructured":"Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244\u20131247, https:\/\/doi.org\/10.1126\/science.1153124 (2008).","journal-title":"Science"},{"key":"33862_CR58","doi-asserted-by":"publisher","first-page":"H1015","DOI":"10.1152\/ajpheart.00023.2006","volume":"291","author":"TA Baudino","year":"2006","unstructured":"Baudino, T. A., Carver, W., Giles, W. & Borg, T. K. Cardiac fibroblasts: friend or foe? American journal of physiology. Heart and circulatory physiology 291, H1015\u20131026, https:\/\/doi.org\/10.1152\/ajpheart.00023.2006 (2006).","journal-title":"American journal of physiology. Heart and circulatory physiology"},{"key":"33862_CR59","doi-asserted-by":"publisher","first-page":"59","DOI":"10.15283\/ijsc.2009.2.1.59","volume":"2","author":"CW Park","year":"2009","unstructured":"Park, C. W. et al. Cytokine secretion profiling of human mesenchymal stem cells by antibody array. Int J Stem Cells 2, 59\u201368 (2009).","journal-title":"Int J Stem Cells"},{"key":"33862_CR60","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/sj.onc.1207162","volume":"23","author":"H Zhao","year":"2004","unstructured":"Zhao, H., Dupont, J., Yakar, S., Karas, M. & LeRoith, D. PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells. Oncogene 23, 786\u2013794, https:\/\/doi.org\/10.1038\/sj.onc.1207162 (2004).","journal-title":"Oncogene"},{"key":"33862_CR61","doi-asserted-by":"publisher","first-page":"2362","DOI":"10.1016\/j.bbadis.2015.08.010","volume":"1852","author":"K Essandoh","year":"2015","unstructured":"Essandoh, K. et al. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim Biophys Acta 1852, 2362\u20132371, https:\/\/doi.org\/10.1016\/j.bbadis.2015.08.010 (2015).","journal-title":"Biochim Biophys Acta"},{"issue":"2","key":"33862_CR62","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1097\/PRS.0000000000004609","volume":"142","author":"Szu-Hsien Wu","year":"2018","unstructured":"Wu, S. H. et al. Therapeutic effects of human adipose-derived products on impaired wound healing in irradiated tissue. Plast Reconstr Surg, https:\/\/doi.org\/10.1097\/PRS.0000000000004609 (2018).","journal-title":"Plastic and Reconstructive Surgery"},{"key":"33862_CR63","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1161\/CIRCRESAHA.117.309417","volume":"120","author":"FAW Coumans","year":"2017","unstructured":"Coumans, F. A. W. et al. Methodological Guidelines to Study Extracellular Vesicles. Circ Res 120, 1632\u20131648, https:\/\/doi.org\/10.1161\/CIRCRESAHA.117.309417 (2017).","journal-title":"Circ Res"},{"key":"33862_CR64","doi-asserted-by":"publisher","first-page":"E968","DOI":"10.1073\/pnas.1521230113","volume":"113","author":"J Kowal","year":"2016","unstructured":"Kowal, J. et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA 113, E968\u2013977, https:\/\/doi.org\/10.1073\/pnas.1521230113 (2016).","journal-title":"Proc Natl Acad Sci USA"},{"key":"33862_CR65","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1093\/cvr\/cvx211","volume":"114","author":"JPG Sluijter","year":"2018","unstructured":"Sluijter, J. P. G. et al. Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 114, 19\u201334, https:\/\/doi.org\/10.1093\/cvr\/cvx211 (2018).","journal-title":"Cardiovasc Res"},{"key":"33862_CR66","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.mam.2017.11.004","volume":"60","author":"SM Davidson","year":"2018","unstructured":"Davidson, S. M. & Yellon, D. M. Exosomes and cardioprotection - A critical analysis. Mol Aspects Med 60, 104\u2013114, https:\/\/doi.org\/10.1016\/j.mam.2017.11.004 (2018).","journal-title":"Mol Aspects Med"},{"key":"33862_CR67","doi-asserted-by":"publisher","first-page":"27031","DOI":"10.3402\/jev.v4.27031","volume":"4","author":"RJ Lobb","year":"2015","unstructured":"Lobb, R. J. et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles 4, 27031, https:\/\/doi.org\/10.3402\/jev.v4.27031 (2015).","journal-title":"J Extracell Vesicles"},{"key":"33862_CR68","doi-asserted-by":"publisher","first-page":"e0145686","DOI":"10.1371\/journal.pone.0145686","volume":"10","author":"T Baranyai","year":"2015","unstructured":"Baranyai, T. et al. Isolation of Exosomes from Blood Plasma: Qualitative and Quantitative Comparison of Ultracentrifugation and Size Exclusion Chromatography Methods. Plos One 10, e0145686, https:\/\/doi.org\/10.1371\/journal.pone.0145686 (2015).","journal-title":"Plos One"},{"key":"33862_CR69","doi-asserted-by":"publisher","first-page":"2407","DOI":"10.1007\/s10616-016-9957-2","volume":"68","author":"P Witek","year":"2016","unstructured":"Witek, P. et al. The effect of a number of H9C2 rat cardiomyocytes passage on repeatability of cytotoxicity study results. Cytotechnology 68, 2407\u20132415, https:\/\/doi.org\/10.1007\/s10616-016-9957-2 (2016).","journal-title":"Cytotechnology"},{"key":"33862_CR70","doi-asserted-by":"publisher","first-page":"e0129303","DOI":"10.1371\/journal.pone.0129303","volume":"10","author":"AF Branco","year":"2015","unstructured":"Branco, A. F. et al. Gene Expression Profiling of H9c2 Myoblast Differentiation towards a Cardiac-Like Phenotype. Plos One 10, e0129303, https:\/\/doi.org\/10.1371\/journal.pone.0129303 (2015).","journal-title":"Plos One"},{"key":"33862_CR71","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.molimm.2017.11.008","volume":"93","author":"L Chen","year":"2018","unstructured":"Chen, L. et al. BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis. Mol Immunol 93, 38\u201346, https:\/\/doi.org\/10.1016\/j.molimm.2017.11.008 (2018).","journal-title":"Mol Immunol"},{"key":"33862_CR72","doi-asserted-by":"publisher","first-page":"e703","DOI":"10.1097\/CCM.0000000000002363","volume":"45","author":"P Jia","year":"2017","unstructured":"Jia, P. et al. MicroRNA-21 Is Required for Local and Remote Ischemic Preconditioning in Multiple Organ Protection Against Sepsis. Crit Care Med 45, e703\u2013e710, https:\/\/doi.org\/10.1097\/CCM.0000000000002363 (2017).","journal-title":"Crit Care Med"},{"key":"33862_CR73","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.pt.2015.06.009","volume":"31","author":"G Coakley","year":"2015","unstructured":"Coakley, G., Maizels, R. M. & Buck, A. H. Exosomes and Other Extracellular Vesicles: The New Communicators in Parasite Infections. Trends Parasitol 31, 477\u2013489, https:\/\/doi.org\/10.1016\/j.pt.2015.06.009 (2015).","journal-title":"Trends Parasitol"},{"key":"33862_CR74","unstructured":"Higgins, J. & Green, S. (editors) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from, handbook.cochrane.org (2011)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-33862-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-33862-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-33862-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T10:52:12Z","timestamp":1671619932000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-33862-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,24]]},"references-count":74,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["33862"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-33862-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,24]]},"assertion":[{"value":"7 August 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"15702"}}