Cardioprotective microRNAs: Lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease

  • Abbas Shapouri Moghaddam
    Department of Immunology, BuAli Research Institute, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
    Search for articles by this author
  • Jalil Tavakol Afshari
    Department of Immunology, BuAli Research Institute, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
    Search for articles by this author
  • Seyed-Alireza Esmaeili
    Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Immunology Department, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
    Search for articles by this author
  • Ehsan Saburi
    Clinical Research Development Center, Imam Hasan Hospital, North Khorasan University of Medical Sciences, Bojnurd, Iran

    Immunogenetic and Cell Culture Department, Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
    Search for articles by this author
  • Zeinab Joneidi
    Department of Genetics and Molecular Medicine, Zanjan University of Medical Science, Iran
    Search for articles by this author
  • Amir Abbas Momtazi-Borojeni
    Corresponding author. Nanotechnology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
    Halal Research Center of IRI, FDA, Tehran, Iran

    Nanotechnology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Department of Medical Biotechnology, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
    Search for articles by this author


      • MSC-derived exosomal miRs can reduce infarct size and improve cardiac survival and function after heart failure.
      • MSC-derived exosomal miRs exert cardioprotective effects through induction of angiogenesis in ischemic heart after MI.
      • CPC-derived exosomal miRs show therapeutic potential for mitral regurgitation, atrial enlargement, and heart failure.


      The stem cell-based therapy has emerged as a promising therapeutic strategy for treating cardiovascular ischemic diseases (CVIDs), such as myocardial infarction (MI). However, some important functional shortcomings of stem cell transplantation, such as immune rejection, tumorigenicity and infusional toxicity, have overshadowed stem cell therapy in the setting of cardiovascular diseases (CVDs). Accumulating evidence suggests that the therapeutic effects of transplanted stem cells are predominately mediated by secreting paracrine factors, importantly, microRNAs (miRs) present in the secreted exosomes. Therefore, novel cell-free therapy based on the stem cell-secreted exosomal miRs can be considered as a safe and effective alternative tool to stem cell therapy for the treatment of CVDs. Stem cell-derived miRs have recently been found to transfer, via exosomes, from a transplanted stem cell into a recipient cardiac cell, where they regulate various cellular process, such as proliferation, apoptosis, stress responses, as well as differentiation and angiogenesis. The present review aimed to summarize cardioprotective exosomal miRs secreted by transplanted stem cells from various sources, including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and cardiac stem/progenitor cells, which showed beneficial modulatory effects on the myocardial infracted heart. In summary, stem cell-exosomal miRs, including miR-19a, mirR-21, miR-21-5p, miR-21-a5p, miR-22 miR-24, miR-26a, miR-29, miR-125b-5p, miR-126, miR-201, miR-210, and miR-294, have been shown to have cardioprotective effects by enhancing cardiomyocyte survival and function and attenuating cardiac fibrosis. Additionally, MCS-exosomal miRs, including miR-126, miR-210, miR-21, miR-23a-3p and miR-130a-3p, are found to exert cardioprotective effects through induction of angiogenesis in ischemic heart after MI.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Organization W.H.
        Global Atlas on Cardiovascular Diseases Prevention and Control.
        2011 (Geneva)
        • Khan J.N.
        • McCann G.P.
        Cardiovascular magnetic resonance imaging assessment of outcomes in acute myocardial infarction.
        World J. Cardiol. 2017; 9: 109-133
        • Plakht Y.
        • Shiyovich A.
        • Gilutz H.
        Predictors of long-term (10-year) mortality postmyocardial infarction: age-related differences. Soroka acute myocardial infarction (SAMI) project.
        J. Cardiol. 2015; 65: 216-223
        • Roth G.A.
        • Huffman M.D.
        • Moran A.E.
        • et al.
        Global and regional patterns in cardiovascular mortality from 1990 to 2013.
        Circulation. 2015; 132: 1667-1678
        • Cantor E.J.
        • Mancini E.V.
        • Seth R.
        • et al.
        Oxidative stress and heart disease: cardiac dysfunction, nutrition, and gene therapy.
        Curr. Hypertens. Rep. 2003; 5: 215-220
        • Lefer D.J.
        • Granger D.N.
        Oxidative stress and cardiac disease.
        Am. J. Med. 2000; 109: 315-323
        • Olivetti G.
        • Quaini F.
        • Sala R.
        • et al.
        Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart.
        J. Mol. Cell. Cardiol. 1996; 28: 2005-2016
        • Buja L.M.
        • Vela D.
        Cardiomyocyte death and renewal in the normal and diseased heart.
        Cardiovasc. Pathol. 2008; 17: 349-374
        • Stayton P.
        • El‐Sayed M.E.
        • Murthy N.
        • et al.
        ‘Smart’delivery systems for biomolecular therapeutics.
        Orthod. Craniofac. Res. 2005; 8: 219-225
        • Srivastava D.
        • Ivey K.N.
        Potential of stem-cell-based therapies for heart disease.
        Nature. 2006; 441: 1097
        • Li X.
        • Hacker M.
        Molecular Imaging in Stem Cell-Based Therapies of Cardiac Diseases.
        Advanced drug delivery reviews, 2017
        • Menasché P.
        • Vanneaux V.
        • Hagège A.
        • et al.
        Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report.
        Eur. Heart J. 2015; 36: 2011-2017
        • Savla J.J.
        • Nelson B.C.
        • Perry C.N.
        • et al.
        Induced pluripotent stem cells for the study of cardiovascular disease.
        J. Am. Coll. Cardiol. 2014; 64: 512-519
        • Golpanian S.
        • Wolf A.
        • Hatzistergos K.E.
        • et al.
        Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue.
        Physiol. Rev. 2016; 96: 1127-1168
        • Majka M.
        • Sułkowski M.
        • Badyra B.
        • et al.
        Concise review: mesenchymal stem cells in cardiovascular regeneration: emerging research directions and clinical applications.
        Stem cells translational medicine. 2017; 6: 1859-1867
      1. Doevendans, PA, Ellison, GM and Chamuleau, SA, Concise Review: Heart Regeneration and the Role of Cardiac Stem Cells.

        • Wang W.E.
        • Chen X.
        • Houser S.R.
        • et al.
        Potential of cardiac stem/progenitor cells and induced pluripotent stem cells for cardiac repair in ischaemic heart disease.
        Clin. Sci. 2013; 125: 319-327
        • Bolli R.
        • Chugh A.R.
        • D'Amario D.
        • et al.
        Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.
        Lancet. 2011; 378: 1847-1857
        • Makkar R.R.
        • Smith R.R.
        • Cheng K.
        • et al.
        Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.
        Lancet. 2012; 379: 895-904
        • Mohsin S.
        • Khan M.
        • Toko H.
        • et al.
        Human cardiac progenitor cells engineered with Pim-I kinase enhance myocardial repair.
        J. Am. Coll. Cardiol. 2012; 60: 1278-1287
        • Tang X.-L.
        • Rokosh G.
        • Sanganalmath S.K.
        • et al.
        Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction.
        Circulation. 2010; 121: 293-305
        • Tang Y.L.
        • Wang Y.J.
        • Chen L.J.
        • et al.
        Cardiac-derived stem cell-based therapy for heart failure: progress and clinical applications.
        Exp. Biol. Med. 2013; 238: 294-300
        • Urbanelli L.
        • Buratta S.
        • Sagini K.
        • et al.
        Exosome-based strategies for diagnosis and therapy.
        Recent Pat. CNS Drug Discov. 2015; 10: 10-27
        • Müller-Ehmsen J.
        • Whittaker P.
        • Kloner R.A.
        • et al.
        Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium.
        J. Mol. Cell. Cardiol. 2002; 34: 107-116
        • Pagani F.D.
        • DerSimonian H.
        • Zawadzka A.
        • et al.
        Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans: histological analysis of cell survival and differentiation.
        J. Am. Coll. Cardiol. 2003; 41: 879-888
        • Cai H.
        • Lin L.
        • Cai H.
        • et al.
        Prognostic evaluation of microRNA-210 expression in pediatric osteosarcoma.
        Med. Oncol. 2013; 30: 499
        • Kishore R.
        • Khan M.
        More than tiny sacks: stem cell exosomes as cell-free modality for cardiac repair.
        Circ. Res. 2016; 118: 330-343
        • Jung J.-H.
        • Fu X.
        • Yang P.C.
        Exosomes generated from iPSC-derivatives: new direction for stem cell therapy in human heart diseases.
        Circ. Res. 2017; 120: 407-417
        • Théry C.
        • Zitvogel L.
        • Amigorena S.
        Exosomes: composition, biogenesis and function.
        Nat. Rev. Immunol. 2002; 2: 569
        • Vahidi Z.
        • Samadi M.
        • Mahmoudi M.
        • et al.
        Lactobacillus rhamnosus and Lactobacillus delbrueckii ameliorate the expression of miR-155 and miR-181a in SLE patients.
        Journal of Functional Foods. 2018; 48: 228-233
        • Valadi H.
        • Ekström K.
        • Bossios A.
        • et al.
        Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.
        Nat. Cell Biol. 2007; 9: 654
        • Stoorvogel W.
        Functional transfer of microRNA by exosomes.
        Blood. 2012; 119: 646-648
        • Arroyo J.D.
        • Chevillet J.R.
        • Kroh E.M.
        • et al.
        Argonaute 2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma.
        Proc. Natl. Acad. Sci. Unit. States Am. 2011; 108: 5003-5008
        • Mittelbrunn M.
        • Gutiérrez-Vázquez C.
        • Villarroya-Beltri C.
        • et al.
        Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells.
        Nat. Commun. 2011; 2: 282
        • Müller G.
        • Jung C.
        • Straub J.
        • et al.
        Induced release of membrane vesicles from rat adipocytes containing glycosylphosphatidylinositol-anchored microdomain and lipid droplet signalling proteins.
        Cell. Signal. 2009; 21: 324-338
        • Sahoo S.
        • Losordo D.W.
        Exosomes and cardiac repair after myocardial infarction.
        Circ. Res. 2014; 114: 333-344
        • Barile L.
        • Gherghiceanu M.
        • Popescu L.M.
        • et al.
        Ultrastructural evidence of exosome secretion by progenitor cells in adult mouse myocardium and adult human cardiospheres.
        2012. BioMed Research International, 2012
        • Frühbeis C.
        • Fröhlich D.
        • Krämer-Albers E.-M.
        Emerging roles of exosomes in neuron–glia communication.
        Front. Physiol. 2012; 3: 119
        • Chen L.
        • Wang Y.
        • Pan Y.
        • et al.
        Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury.
        Biochemical and biophysical research communications. 2013; 431: 566-571
        • Sahoo S.
        • Klychko E.
        • Thorne T.
        • et al.
        Exosomes from human CD34+ stem cells mediate their proangiogenic paracrine activity.
        Circ. Res. 2011; 109: 724-728
        • Vrijsen K.
        • Sluijter J.
        • Schuchardt M.
        • et al.
        Cardiomyocyte progenitor cell‐derived exosomes stimulate migration of endothelial cells.
        J. Cell Mol. Med. 2010; 14: 1064-1070
        • Ong S.-G.
        • Lee W.H.
        • Huang M.
        • et al.
        Cross talk of combined gene and cell therapy in ischemic heart disease: role of exosomal microRNA transfer.
        Circulation. 2014; 130: S60-S69
        • Mackie A.R.
        • Klyachko E.
        • Thorne T.
        • et al.
        Sonic hedgehog–modified human CD34+ cells preserve cardiac function after acute myocardial infarction, Circulation research.
        Circresaha. 2012; 112: 266015
        • Lai R.C.
        • Arslan F.
        • Lee M.M.
        • et al.
        Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury.
        Stem Cell Res. 2010; 4: 214-222
        • Ibrahim A.G.-E.
        • Cheng K.
        • Marbán E.
        Exosomes as critical agents of cardiac regeneration triggered by cell therapy.
        Stem cell reports. 2014; 2: 606-619
        • Arslan F.
        • Lai R.C.
        • Smeets M.B.
        • 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
        • Lai R.C.
        • Arslan F.
        • Lee M.M.
        • et al.
        Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury.
        Stem Cell Res. 2010; 4: 214-222
        • Yu B.
        • Kim H.W.
        • Gong M.
        • et al.
        Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection.
        Int. J. Cardiol. 2015; 182: 349-360
        • Katsuda T.
        • Kosaka N.
        • Takeshita F.
        • et al.
        The therapeutic potential of mesenchymal stem cell‐derived extracellular vesicles.
        Proteomics. 2013; 13: 1637-1653
        • Yellon D.M.
        • Davidson S.M.
        Exosomes: nanoparticles involved in cardioprotection?.
        Circ. Res. 2014; 114: 325-332
        • 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. 2014; 92: 387-397
        • Teng X.
        • Chen L.
        • Chen W.
        • et al.
        Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation.
        Cell. Physiol. Biochem. 2015; 37: 2415-2424
        • Boomsma R.A.
        • Geenen D.L.
        Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis.
        PLoS One. 2012; 7e35685
        • Kishore R.
        • Khan M.
        Cardiac Cell-Derived Exosomes: Changing Face of Regenerative Biology. Oxford University Press, 2016
        • Tang Y.-T.
        • Huang Y.-Y.
        • Zheng L.
        • et al.
        Comparison of isolation methods of exosomes and exosomal RNA from cell culture medium and serum.
        Int. J. Mol. Med. 2017; 40: 834-844
        • Yuan Y.
        • Du W.
        • Liu J.
        • et al.
        Stem cell-derived exosome in cardiovascular diseases: macro roles of micro particles.
        Front. Pharmacol. 2018; 9
        • Miao Q.
        • Shim W.
        • Tee N.
        • et al.
        iPSC‐derived human mesenchymal stem cells improve myocardial strain of infarcted myocardium.
        J. Cell Mol. Med. 2014; 18: 1644-1654
        • Motavaf M.
        • Pakravan K.
        • Babashah S.
        • et al.
        Therapeutic application of mesenchymal stem cell-derived exosomes: a promising cell-free therapeutic strategy in regenerative medicine.
        Cell. Mol. Biol. 2016; 62: 74-79
        • Desrochers L.M.
        • Bordeleau F.
        • Reinhart-King C.A.
        • et al.
        Microvesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation.
        Nat. Commun. 2016; 7: 11958
        • Loyer X.
        • Vion A.-C.
        • Tedgui A.
        • et al.
        Microvesicles as cell–cell messengers in cardiovascular diseases.
        Circ. Res. 2014; 114: 345-353
        • Marote A.
        • Teixeira F.G.
        • Mendes-Pinheiro B.
        • et al.
        MSCs-derived exosomes: cell-secreted nanovesicles with regenerative potential.
        Front. Pharmacol. 2016; 7: 231
        • Sluijter J.P.
        • Van Rooij E.
        Exosomal microRNA Clusters Are Important for the Therapeutic Effect of Cardiac Progenitor Cells. Am Heart Assoc, 2015
        • Yuan M.
        • Zhang L.
        • You F.
        • et al.
        MiR-145-5p regulates hypoxia-induced inflammatory response and apoptosis in cardiomyocytes by targeting CD40.
        Mol. Cell. Biochem. 2017; 431: 123-131
        • Yang J.
        • Brown M.E.
        • Zhang H.
        • et al.
        High-throughput screening identifies microRNAs that target Nox 2 and improve function after acute myocardial infarction.
        Am. J. Physiol. Heart Circ. Physiol. 2017; 312: H1002-h1012
        • Barwari T.
        • Joshi A.
        • Mayr M.
        MicroRNAs in cardiovascular disease.
        J. Am. Coll. Cardiol. 2016; 68: 2577-2584
        • Gray W.D.
        • French K.M.
        • Ghosh-Choudhary S.
        • et al.
        Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology.
        Circ. Res. 2015; 116: 255-263
        • Boyd S.D.
        Everything you wanted to know about small RNA but were afraid to ask.
        Lab. Invest. 2008; 88: 569
        • Bartel D.P.
        MicroRNAs: genomics, biogenesis, mechanism, and function.
        Cell. 2004; 116: 281-297
        • Dweep H.
        • Gretz N.
        • Sticht C.
        miRWalk database for miRNA–target interactions.
        in: RNA Mapping. Springer, 2014: 289-305
        • Condorelli G.
        • Latronico M.V.G.
        • Cavarretta E.
        microRNAs in cardiovascular diseases: current knowledge and the road ahead.
        J. Am. Coll. Cardiol. 2014; 63: 2177-2187
        • Quiat D.
        • Olson E.N.
        MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment.
        J. Clin. Investig. 2013; 123: 11-18
        • Maegdefessel L.
        The emerging role of micro RNA s in cardiovascular disease.
        J. Intern. Med. 2014; 276: 633-644
        • van Rooij E.
        • Sutherland L.B.
        • Thatcher J.E.
        • et al.
        Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.
        Proc. Natl. Acad. Sci. Unit. States Am. 2008; 105: 13027-13032
        • Tao L.
        • Bei Y.
        • Zhou Y.
        • et al.
        Non-coding RNAs in cardiac regeneration.
        Oncotarget. 2015; 6: 42613
        • Liu X.
        • Hong Q.
        • Wang Z.
        • et al.
        MiR-21 inhibits autophagy by targeting Rab11a in renal ischemia/reperfusion.
        Exp. Cell Res. 2015; 338: 64-69
        • Lv G.
        • Shao S.
        • Dong H.
        • et al.
        MicroRNA‐214 protects cardiac myocytes against H2O2‐induced injury.
        J. Cell. Biochem. 2014; 115: 93-101
        • Prabhu S.D.
        • Frangogiannis N.G.
        The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis.
        Circ. Res. 2016; 119: 91-112
        • Li X.
        • Kong M.
        • Jiang D.
        • et al.
        MicroRNA-150 aggravates H2O2-induced cardiac myocyte injury by down-regulating c-myb gene.
        Acta Biochim. Biophys. Sin. 2013; 45: 734-741
        • Cha M.-J.
        • Jang J.-K.
        • Ham O.
        • et al.
        MicroRNA-145 suppresses ROS-induced Ca 2+ overload of cardiomyocytes by targeting CaMKIIδ.
        Biochemical and biophysical research communications. 2013; 435: 720-726
        • Saparov A.
        • Ogay V.
        • Nurgozhin T.
        • et al.
        Role of the immune system in cardiac tissue damage and repair following myocardial infarction.
        Inflamm. Res. 2017; 66: 739-751
        • Duisters R.F.
        • Tijsen A.J.
        • Schroen B.
        • et al.
        miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling.
        Circ. Res. 2009; 104: 170-178
        • Mathiasen A.B.
        • Haack-Sørensen M.
        • Jørgensen E.
        • et al.
        Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina—final 3-year follow-up.
        Int. J. Cardiol. 2013; 170: 246-251
        • Perin E.C.
        • Silva G.V.
        • Henry T.D.
        • et al.
        A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF).
        Am. Heart J. 2011; 161 (e1073): 1078-1087
        • Karantalis V.
        • Hare J.M.
        Use of mesenchymal stem cells for therapy of cardiac disease.
        Circ. Res. 2015; 116: 1413-1430
        • Hare J.M.
        • DiFede D.L.
        • Rieger A.C.
        • et al.
        Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM trial.
        J. Am. Coll. Cardiol. 2017; 69: 526-537
        • Heldman A.W.
        • DiFede D.L.
        • Fishman J.E.
        • et al.
        Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial.
        Jama. 2014; 311: 62-73
        • Meyer G.P.
        • Wollert K.C.
        • Lotz J.
        • et al.
        Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial.
        Eur. Heart J. 2009; 30: 2978-2984
        • Fisher S.A.
        • Doree C.
        • Mathur A.
        • et al.
        Meta-Analysis of cell therapy trials for patients with heart failure-an update, circulation research.
        Circresaha. 2015; 114: 304386
        • Ahuja P.
        • Perriard E.
        • Perriard J.-C.
        • et al.
        Sequential myofibrillar breakdown accompanies mitotic division of mammalian cardiomyocytes.
        J. Cell Sci. 2004; 117: 3295-3306
        • 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: 970-983
        • Li Y.
        • Shen Z.
        • Yu X.-Y.
        Transport of microRNAs via exosomes.
        Nat. Rev. Cardiol. 2015; 12: 198
        • Boon R.A.
        • Dimmeler S.
        MicroRNAs in myocardial infarction.
        Nat. Rev. Cardiol. 2015; 12: 135
        • Timmers L.
        • Lim S.K.
        • Arslan F.
        • et al.
        Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium.
        Stem Cell Res. 2008; 1: 129-137
        • Mayourian J.
        • Ceholski D.K.
        • Gorski P.
        • et al.
        Exosomal microRNA-21-5p mediates mesenchymal stem cell paracrine effects on human cardiac tissue contractility.
        Circ. Res. 2018; 118 (Circresaha): 312420
        • Luther K.M.
        • Haar L.
        • McGuinness M.
        • et al.
        Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells.
        J. Mol. Cell. Cardiol. 2018; 119: 125-137
        • 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; 9e88685
        • Katare R.
        • Riu F.
        • Mitchell K.
        • et al.
        Transplantation of Human Pericyte Progenitor Cells Improves the Repair of Infarcted Heart through Activation of an Angiogenic Program Involving Micro-RNA-132, Circulation Research.
        Circresaha. 2011; vol. 111: 251546
        • Alvarez-Saavedra M.
        • Carrasco L.
        • Sura-Trueba S.
        • et al.
        Elevated expression of MeCP2 in cardiac and skeletal tissues is detrimental for normal development.
        Hum. Mol. Genet. 2010; 19: 2177-2190
        • Shao L.
        • Zhang Y.
        • Lan B.
        • et al.
        MiRNA-sequence Indicates that Mesenchymal Stem Cells and Exosomes Have Similar Mechanism to Enhance Cardiac Repair. vol. 2017. BioMed research international, 2017
        • Qian L.
        • Van Laake L.W.
        • Huang Y.
        • et al.
        miR-24 inhibits apoptosis and represses Bim in mouse cardiomyocytes.
        J. Exp. Med. 2011; 208: 549-560
        • Wang B.
        • Komers R.
        • Carew R.
        • et al.
        Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis.
        J. Am. Soc. Nephrol. 2012; 23: 252-265
        • Boon R.A.
        • Iekushi K.
        • Lechner S.
        • et al.
        MicroRNA-34a regulates cardiac ageing and function.
        Nature. 2013; 495: 107
        • Bernardo B.C.
        • Gao X.-M.
        • Winbanks C.E.
        • et al.
        Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function.
        Proc. Natl. Acad. Sci. Unit. States Am. 2012; 109: 17615-17620
        • Li Y.
        • Yang C.-M.
        • Xi Y.
        • et al.
        MicroRNA-1/133 targeted dysfunction of potassium channels KCNE1 and KCNQ1 in human cardiac progenitor cells with simulated hyperglycemia.
        Int. J. Cardiol. 2013; 167: 1076-1078
        • Ganesan J.
        • Ramanujam D.
        • Sassi Y.
        • et al.
        MiR-378 controls cardiac hypertrophy by combined repression of MAP kinase pathway factors, Circulation.
        Circulationaha. 2013; 112000882
        • Bang C.
        • Batkai S.
        • Dangwal S.
        • et al.
        Cardiac fibroblast–derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy.
        J. Clin. Investig. 2014; 124: 2136-2146
        • Hullinger T.G.
        • Montgomery R.L.
        • Seto A.G.
        • et al.
        Inhibition of miR-15 protects against cardiac ischemic injurynovelty and significance.
        Circ. Res. 2012; 110: 71-81
        • Hu X.
        • Wu R.
        • Shehadeh L.A.
        • et al.
        Severe hypoxia exerts parallel and cell-specific regulation of gene expression and alternative splicing in human mesenchymal stem cells.
        BMC Genomics. 2014; 15: 303
        • Hu X.
        • Wu R.
        • Jiang Z.
        • et al.
        Leptin signaling is required for augmented therapeutic properties of mesenchymal stem cells conferred by hypoxia preconditioning.
        Stem Cell. 2014; 32: 2702-2713
        • 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: 736-745
        • 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.
        Artificial cells, nanomedicine, and biotechnology. 2017; : 1-12
        • Luo Q.
        • Guo D.
        • Liu G.
        • et al.
        Exosomes from mir-126-overexpressing adscs are therapeutic in relieving acute myocardial ischaemic injury.
        Cell. Physiol. Biochem. 2017; 44: 2105-2116
        • Xiao C.
        • Wang K.
        • Xu Y.
        • et al.
        Transplanted mesenchymal stem cells reduce autophagic flux in infarcted hearts via the exosomal transfer of mir-125b, circulation research.
        Circresaha. 2018; 118: 312758
        • Buss S.J.
        • Riffel J.H.
        • Katus H.A.
        • et al.
        Augmentation of autophagy by mTOR-inhibition in myocardial infarction: when size matters.
        Autophagy. 2010; 6: 304-306
        • Kanamori H.
        • Takemura G.
        • Goto K.
        • et al.
        Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion.
        Am. J. Physiol. Heart Circ. Physiol. 2011; 300: H2261-H2271
        • Matsui Y.
        • Takagi H.
        • Qu X.
        • et al.
        Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy.
        Circ. Res. 2007; 100: 914-922
        • Nah J.
        • Fernández Á.F.
        • Kitsis R.N.
        • et al.
        Does autophagy mediate cardiac myocyte death during stress?.
        Circ. Res. 2016; 119: 893-895
        • Denton D.
        • Nicolson S.
        • Kumar S.
        Cell death by autophagy: facts and apparent artefacts.
        Cell Death Differ. 2012; 19: 87
        • Gao T.
        • Zhang S.P.
        • Wang J.F.
        • et al.
        TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction.
        J. Cell Mol. Med. 2018; 22: 395-408
        • Ahmed M.I.
        • Gladden J.D.
        • Litovsky S.H.
        • et al.
        Increased oxidative stress and cardiomyocyte myofibrillar degeneration in patients with chronic isolated mitral regurgitation and ejection fraction> 60%.
        J. Am. Coll. Cardiol. 2010; 55: 671-679
        • Chen M.-C.
        • Chang J.-P.
        • Liu W.-H.
        • et al.
        Increased serum oxidative stress in patients with severe mitral regurgitation: a new finding and potential mechanism for atrial enlargement.
        Clin. Biochem. 2009; 42: 943-948
        • Hare J.M.
        • Mangal B.
        • Brown J.
        • et al.
        Impact of oxypurinol in patients with symptomatic heart failure: results of the OPT-CHF study.
        J. Am. Coll. Cardiol. 2008; 51: 2301-2309
        • Xiao J.
        • Pan Y.
        • Li X.
        • et al.
        Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4.
        Cell Death Dis. 2016; 7: e2277
        • Liwak-Muir U.
        • Dobson C.C.
        • Naing T.
        • et al.
        ERK8 is a novel HuR kinase that regulates tumour suppressor PDCD4 through a miR-21 dependent mechanism.
        Oncotarget. 2016; 7: 1439
        • Chen L.
        • Wang Y.
        • Pan Y.
        • et al.
        Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury.
        Biochem. Biophys. Res. Commun. 2013; 431: 566-571
        • Mayhall E.A.
        • Paffett-Lugassy N.
        • Zon L.I.
        The clinical potential of stem cells.
        Curr. Opin. Cell Biol. 2004; 16: 713-720
        • Laflamme M.A.
        • Chen K.Y.
        • Naumova A.V.
        • et al.
        Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts.
        Nat. Biotechnol. 2007; 25: 1015
        • Chong J.J.
        • Yang X.
        • Don C.W.
        • et al.
        Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.
        Nature. 2014; 510: 273
        • Blin G.
        • Nury D.
        • Stefanovic S.
        • et al.
        A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates.
        J. Clin. Investig. 2010; 120: 1125-1139
        • Caspi O.
        • Huber I.
        • Kehat I.
        • et al.
        Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts.
        J. Am. Coll. Cardiol. 2007; 50: 1884-1893
      2. Elrod, GQ, Houser, SR, Koch, WJ, et al., Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction.

        • Wang Y.
        • Zhang L.
        • Li Y.
        • et al.
        Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium.
        Int. J. Cardiol. 2015; 192: 61-69
        • Yu J.-M.
        • Zhang X.-B.
        • Jiang W.
        • et al.
        Astragalosides promote angiogenesis via vascular endothelial growth factor and basic fibroblast growth factor in a rat model of myocardial infarction.
        Mol. Med. Rep. 2015; 12: 6718-6726
        • Garikipati V.N.S.
        • Krishnamurthy P.
        • Verma S.K.
        • et al.
        Negative regulation of miR‐375 by interleukin‐10 enhances bone marrow‐derived progenitor cell‐mediated myocardial repair and function after myocardial infarction.
        Stem Cell. 2015; 33: 3519-3529
        • Esser J.S.
        • Saretzki E.
        • Pankratz F.
        • et al.
        Bone morphogenetic protein 4 regulates microRNAs miR-494 and miR-126–5p in control of endothelial cell function in angiogenesis.
        Thromb. Haemostasis. 2017; 117: 734-749
        • Zhang J.
        • Sun X.-J.
        • Chen Ja
        • et al.
        Increasing the miR-126 expression in the peripheral blood of patients with diabetic foot ulcers treated with maggot debridement therapy.
        J. Diabetes Complicat. 2017; 31: 241-244
        • Tao S.C.
        • Guo S.C.
        • Li M.
        • et al.
        Chitosan wound dressings incorporating exosomes derived from MicroRNA‐126‐overexpressing synovium mesenchymal stem cells provide sustained release of exosomes and heal full‐thickness skin defects in a diabetic rat model.
        Stem cells translational medicine. 2017; 6: 736-747
        • Guo C.
        • Sah J.F.
        • Beard L.
        • et al.
        The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers.
        Genes Chromosomes Cancer. 2008; 47: 939-946
        • Wang S.
        • Aurora A.B.
        • Johnson B.A.
        • et al.
        The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis.
        Dev. Cell. 2008; 15: 261-271
        • Banerjee N.
        • Kim H.
        • Talcott S.
        • et al.
        Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR.
        Carcinogenesis. 2013; 34: 2814-2822
        • Angel-Morales G.
        • Noratto G.
        • Mertens-Talcott S.
        Red wine polyphenolics reduce the expression of inflammation markers in human colon-derived CCD-18Co myofibroblast cells: potential role of microRNA-126.
        Food & function. 2012; 3: 745-752
        • Wang N.
        • Chen C.
        • Yang D.
        • et al.
        Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis.
        Biochim. Biophys. Acta (BBA) - Mol. Basis Dis. 2017; 1863: 2085-2092
        • Hu S.
        • Huang M.
        • Li Z.
        • et al.
        MicroRNA-210 as a novel therapy for treatment of ischemic heart disease.
        Circulation. 2010; 122: S124-S131
        • Fasanaro P.
        • D'Alessandra Y.
        • Di Stefano V.
        • et al.
        MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3.
        J. Biol. Chem. 2008; 283: 15878-15883
        • Xiao F.
        • Qiu H.
        • Zhou L.
        • et al.
        WSS25 inhibits Dicer, downregulating microRNA-210, which targets Ephrin-A3, to suppress human microvascular endothelial cell (HMEC-1) tube formation.
        Glycobiology. 2013; 23: 524-535
        • Wang K.
        • Jiang Z.
        • Webster K.A.
        • et al.
        Enhanced cardioprotection by human endometrium mesenchymal stem cells driven by exosomal microRNA‐21.
        Stem cells translational medicine. 2017; 6: 209-222
        • Ferguson S.W.
        • Wang J.
        • Lee C.J.
        • et al.
        The microRNA regulatory landscape of MSC-derived exosomes: a systems view.
        Sci. Rep. 2018; 8: 1419
        • Chen Y.
        • Gorski D.H.
        Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5.
        Blood. 2008; 111: 1217-1226