Exosomes in Myocardial Repair: Advances and Challenges in the Development of Next-Generation Therapeutics
Authors: Marta Adamiak, Susmita Sahoo
Journal: Molecular Therapy (2018)

Myocardial disease is a leading cause of morbidity and mortality worldwide. Given the limited regenerative capacity of the human heart following myocardial injury, stem cell-based therapies have emerged as a promising approach for improving cardiac repair and function. The discovery of extracellular vesicles including exosomes as a key component of the beneficial function of stem cells has generated hope for their use to advance cell-based regenerative therapies for cardiac repair. Exosomes secreted from stem cells are membranous bionanovesicles, naturally loaded with various proteins, lipids, and nucleic acids. They have been found to have anti-apoptotic, anti-fibrotic, as well as pro-angiogenic effects, all of which are crucial to restore function of the damaged myocardium. In this brief review, we will focus on the latest research and debates on cardiac repair and regenerative potential of exosomes from a variety of sources such as cardiac and non-cardiac stem and progenitor cells, somatic cells, and body fluids. We will also highlight important barriers involved in translating these findings into developing clinically suitable exosome-based therapies. Myocardial disease is a leading cause of morbidity and mortality worldwide. Given the limited regenerative capacity of the human heart following myocardial injury, stem cell-based therapies have emerged as a promising approach for improving cardiac repair and function. The discovery of extracellular vesicles including exosomes as a key component of the beneficial function of stem cells has generated hope for their use to advance cell-based regenerative therapies for cardiac repair. Exosomes secreted from stem cells are membranous bionanovesicles, naturally loaded with various proteins, lipids, and nucleic acids. They have been found to have anti-apoptotic, anti-fibrotic, as well as pro-angiogenic effects, all of which are crucial to restore function of the damaged myocardium. In this brief review, we will focus on the latest research and debates on cardiac repair and regenerative potential of exosomes from a variety of sources such as cardiac and non-cardiac stem and progenitor cells, somatic cells, and body fluids. We will also highlight important barriers involved in translating these findings into developing clinically suitable exosome-based therapies. According to the World Health Organization (WHO), cardiovascular diseases (CVDs) represent a group of disorders associated with the loss of cardiac function and remain a major cause of morbidity and mortality worldwide. In spite of therapeutic intervention advances, 17.7 million people die each year of CVDs, an estimated 31% of all deaths worldwide.1World Health OrganizationCardiovascular disease.http://www.who.int/cardiovascular_diseases/en/Date: 2017Google Scholar Most strikingly, CVDs claim more lives each year than all forms of cancer and chronic lower respiratory disease combined.2Benjamin E.J. Blaha M.J. Chiuve S.E. Cushman M. Das S.R. Deo R. de Ferranti S.D. Floyd J. Fornage M. Gillespie C. et al.American Heart Association Statistics Committee and Stroke Statistics SubcommitteeHeart disease and stroke statistics—2017 update: a report from the American Heart Association.Circulation. 2017; 135: e146-e603Crossref PubMed Scopus (6298) Google Scholar Because of unhealthy ways of life (tobacco use, unhealthy diet, physical inactivity, and the harmful use of alcohol) and the phenomenon of population aging, which contribute to increased risk factors, the number of deaths from CVDs is expected to rise in the near future. Although the events leading to CVDs are miscellaneous, a fundamental problem is the presence of scar tissue and the irreversible loss of cardiac muscle cells, which dynamically contribute to alterations in ventricular contractility and relaxation. Since the first study reported in 1998 indicating the ability of skeletal muscle to repair the heart,3Taylor D.A. Atkins B.Z. Hungspreugs P. Jones T.R. Reedy M.C. Hutcheson K.A. Glower D.D. Kraus W.E. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation.Nat. Med. 1998; 4: 929-933Crossref PubMed Scopus (999) Google Scholar a spectrum of stem cells has been investigated for treatment of CVDs. The most studied cell types are skeletal myoblasts (SKMs), bone marrow-derived cells (BMCs), induced pluripotent stem cells (iPSCs), endothelial progenitor cells (EPCs), and cardiac progenitor cells (CPCs). Cardiac stem cell (CSC) therapy possesses several major challenges for researchers and clinicians, which include immune rejection after transplantation, poor engraftment and survival of the transplanted cells, occurrence of ventricular arrhythmias, and risk for tumor formation.4Cambria E. Pasqualini F.S. Wolint P. Günter J. Steiger J. Bopp A. Hoerstrup S.P. Emmert M.Y. Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types.NPJ Regen. Med. 2017; 2: 17Crossref PubMed Google Scholar Nevertheless, alternative options, such as a cell-free approach, have emerged as potential new therapeutic strategies that mimic the benefit of cell therapy without the need for cell transplantation. In particular, exosome-based therapy has become a new focal point for the treatment of CVDs. Here, we discuss the utility of exosomes as cell-free therapeutic candidates that can mediate cardiac repair. To provide the reader with the recent progress in the field, we present the most relevant results, as well as current limitations and challenges associated with exosome-based therapy. In multicellular organisms, cells can exchange information with neighboring or distant cells by sending out signals composed of single molecules or via membrane vesicles called extracellular vesicles (EVs). EVs are composed of a lipid bilayer containing transmembrane proteins and enclosing cytosolic proteins and various nucleic acids (including mRNAs, microRNAs [miRNAs], and other non-coding RNAs [ncRNAs]).5Tkach M. Théry C. Communication by extracellular vesicles: where we are and where we need to go.Cell. 2016; 164: 1226-1232Abstract Full Text Full Text PDF PubMed Scopus (2023) Google Scholar, 6Shurtleff M.J. Yao J. Qin Y. Nottingham R.M. Temoche-Diaz M.M. Schekman R. Lambowitz A.M. Broad role for YBX1 in defining the small noncoding RNA composition of exosomes.Proc. Natl. Acad. Sci. USA. 2017; 114: E8987-E8995Crossref PubMed Scopus (191) Google Scholar, 7Valadi H. Ekström K. Bossios A. Sjöstrand M. Lee J.J. Lötvall J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.Nat. Cell Biol. 2007; 9: 654-659Crossref PubMed Scopus (8923) Google Scholar Cells can secrete different types of EVs that have been classified according to their subcellular origin. Current research interest in the field of EVs focuses primarily on vesicles of endosomal and plasma membrane origin called exosomes and microvesicles (or ectosomes), respectively.8Maas S.L.N. Breakefield X.O. Weaver A.M. Extracellular vesicles: unique intercellular delivery vehicles.Trends Cell Biol. 2017; 27: 172-188Abstract Full Text Full Text PDF PubMed Scopus (812) Google Scholar Exosomes, typically ranging between 30 and 100 nm in size, originate from the inward budding of the membrane of endosomal vesicles called multivesicular bodies (MVBs) and are exported out of the cell after fusion of MVBs with the plasma membrane.8Maas S.L.N. Breakefield X.O. Weaver A.M. Extracellular vesicles: unique intercellular delivery vehicles.Trends Cell Biol. 2017; 27: 172-188Abstract Full Text Full Text PDF PubMed Scopus (812) Google Scholar, 9Théry C. Zitvogel L. Amigorena S. Exosomes: composition, biogenesis and function.Nat. Rev. Immunol. 2002; 2: 569-579Crossref PubMed Scopus (3754) Google Scholar Owing to their highly regulated biogenesis, exosomes have been proposed to differ from other EVs by their specific membranous and cytosolic composition. Exosomes bear surface molecules that allow them to be specifically targeted to other cells. Once attached to a recipient cell, vesicles can induce signaling via receptor-ligand interaction or can be internalized by endocytosis and/or phagocytosis, or even fuse with the target cell membrane to deliver their content into cytosol, thereby altering the physiological state of the recipient cell.7Valadi H. Ekström K. Bossios A. Sjöstrand M. Lee J.J. Lötvall J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.Nat. Cell Biol. 2007; 9: 654-659Crossref PubMed Scopus (8923) Google Scholar, 10Mulcahy L.A. Pink R.C. Carter D.R. Routes and mechanisms of extracellular vesicle uptake.J. Extracell. Vesicles. 2014; 3: 1Crossref Scopus (1502) Google Scholar, 11Alvarez-Erviti L. Seow Y. Yin H. Betts C. Lakhal S. Wood M.J. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.Nat. Biotechnol. 2011; 29: 341-345Crossref PubMed Scopus (2978) Google Scholar EVs are secreted by almost every cell type, including endothelial cells, neuronal cells, smooth muscle cells, tumor cells, and stem cells, and are detected in most body fluids, such as urine, blood, saliva, cerebrospinal fluid, as well as ascites. Recently, cell- and body fluid-derived EVs have gained attention as highly bioactive, acellular carriers in a wide variety of biomedical applications, including heart tissue repair.12Liang Y. Sahoo S. Exosomes explosion for cardiac resuscitation.J. Am. Coll. Cardiol. 2015; 66: 612-615Crossref PubMed Scopus (11) Google Scholar, 13Sahoo S. Losordo D.W. Exosomes and cardiac repair after myocardial infarction.Circ. Res. 2014; 114: 333-344Crossref PubMed Scopus (361) Google Scholar Table 1 summarizes the utility of exosomes in therapy applications for cardiovascular repair, proven in various animal in vivo models.Table 1Exosome Therapy for Cardiovascular Repair in Animal In Vivo ModelsVesicle Source/Donor Cell Phenotype ModificationSpecies/Type of Injury or In Vivo AssayExosomal miRNA/Proteins InvolvedFunction of Exosomes/Study HighlightsReferencesStem Cell-Derived ExosomesMurine iPSCsmouse, I/R injuryglobal miRNA and proteomic profiling performedimproved LV function, reduced CM apoptosis, and enhanced angiogenesis14Adamiak M. Cheng G. Bobis-Wozowicz S. Zhao L. Kedracka-Krok S. Samanta A. Karnas E. Xuan Y.T. Skupien-Rabian B. Chen X. et al.Induced pluripotent stem cell (iPSC)-derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs.Circ. Res. 2018; 122: 296-309Crossref PubMed Scopus (155) Google ScholarmiR-21 and miR-210protection of ischemic CMs from apoptosis; no significant change in cardiac function65Wang Y. Zhang L. Li Y. Chen L. Wang X. Guo W. Zhang X. Qin G. He S.H. Zimmerman A. 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: 61-69Abstract Full Text Full Text PDF PubMed Scopus (292) Google ScholarMurine ESCsmouse, acute MImiR-294-3pimproved post-MI cardiac function and neovascularization; augmented CM proliferation and survival; promoted CPC survival, proliferation, persistence, and contribution toward repair processes in the heart15Khan M. Nickoloff E. Abramova T. Johnson J. Verma S.K. Krishnamurthy P. Mackie A.R. Vaughan E. Garikipati V.N. Benedict C. et al.Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction.Circ. Res. 2015; 117: 52-64Crossref PubMed Scopus (492) Google ScholarHuman EnMSCsrat, MImiR-21, with downstream effects on the target PTEN-Akt survival pathwayenhanced myocardial salvage and microvessel regeneration, improved cardiac function; note: EnMSCs were injected in this study, inhibitor studies indicated that the actions of EnMSCs were mediated by secreted Exo16Wang K. Jiang Z. Webster K.A. Chen J. Hu H. Zhou Y. Zhao J. Wang L. Wang Y. Zhong Z. et al.Enhanced cardioprotection by human endometrium mesenchymal stem cells driven by exosomal microRNA-21.Stem Cells Transl. Med. 2017; 6: 209-222Crossref PubMed Scopus (180) Google ScholarHuman UC-MSCs; Akt gene-modifiedrat, acute MIPDGFDimproved cardiac function and promoted blood vessel formation17Ma J. Zhao Y. Sun L. Sun X. Zhao X. Sun X. Qian H. Xu W. Zhu W. Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D.Stem Cells Transl. Med. 2017; 6: 51-59Crossref PubMed Scopus (204) Google ScholarMurine BM-MSCs; cultured under hypoxic or normoxic conditionsmouse, MImiRNA-210 (in an nSMase2-dependent way)improved cardiac function, reduced scar size and fibrosis, decreased CM apoptosis, increased vascular density and recruitment of CPCs in the infarcted heart18Zhu J. Lu K. Zhang N. Zhao Y. Ma Q. Shen J. Lin Y. Xiang P. Tang Y. Hu X. et al.Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way.Artif. Cells Nanomed. Biotechnol. 2017; (Published online November 16, 2017)https://doi.org/10.1080/21691401.2017.1388249Crossref Scopus (138) Google ScholarRat CDCsrat, chronic MIno data availableincreased global pump function and vessel density, reduced scar mass; note: Exo-primed or -unprimed dermal fibroblasts were injected in this study22Tseliou E. Fouad J. Reich H. Slipczuk L. de Couto G. Aminzadeh M. Middleton R. Valle J. Weixin L. Marbán E. Fibroblasts rendered antifibrotic, antiapoptotic, and angiogenic by priming with cardiosphere-derived extracellular membrane vesicles.J. Am. Coll. Cardiol. 2015; 66: 599-611Crossref PubMed Scopus (98) Google ScholarHuman CDCsmouse, acute and chronic MImiR-146aimproved cardiac function, imparted structural benefits, and increased viable mass23Ibrahim A.G. Cheng K. Marbán E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy.Stem Cell Reports. 2014; 2: 606-619Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholarpig, I/R injury (IC or IM delivery) and CMI (IM delivery)no data availabledecreased infarct size and preserved LV function (I/R injury, only IM delivery); preserved LV volumes and function, decreased scar size, decreased LV collagen content and CM hypertrophy, increased vessel density (CMI, IM delivery)24Gallet R. Dawkins J. Valle J. Simsolo E. de Couto G. Middleton R. Tseliou E. Luthringer D. Kreke M. Smith R.R. et al.Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction.Eur. Heart J. 2017; 38: 201-211PubMed Google ScholarHuman (neonate, infant, child) c-kit+ CPCs; cultured under hypoxic or normoxic conditionsrat, I/R injurycomputational modeling of miRNAs performedimproved cardiac function (hypoxic and neonate CPC-derived Exo); improved fibrosis and angiogenesis (hypoxic CPC-derived Exo); improved hypertrophy (CPC-derived Exo)30Agarwal U. George A. Bhutani S. Ghosh-Choudhary S. Maxwell J.T. Brown M.E. Mehta Y. Platt M.O. Liang Y. Sahoo S. Davis M.E. Experimental, systems, and computational approaches to understanding the microRNA-mediated reparative potential of cardiac progenitor cell-derived exosomes from pediatric patients.Circ. Res. 2017; 120: 701-712Crossref PubMed Scopus (122) Google ScholarHuman CD34+ PBMCsmouse, LImiR-126-3penhanced therapeutic recovery and vascular angiogenesis32Mathiyalagan P. Liang Y. Kim D. Misener S. Thorne T. Kamide C.E. Klyachko E. Losordo D.W. Hajjar R.J. Sahoo S. Angiogenic mechanisms of human CD34+ stem cell exosomes in the repair of ischemic hindlimb.Circ. Res. 2017; 120: 1466-1476Crossref PubMed Scopus (168) Google Scholarmouse, in vivo Matrigel plug assaymiR-126stimulated angiogenesis66Mocharla P. Briand S. Giannotti G. Dörries C. Jakob P. Paneni F. Lüscher T. Landmesser U. AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics.Blood. 2013; 121: 226-236Crossref PubMed Scopus (154) Google ScholarHuman CD34+ PBMCs; SHH gene-modifiedmouse, acute MISHHreduced infarct size and increased border zone capillary density; note: CD34+ cells were injected in this study, in vitro studies indicated that the actions of CD34+ cells were mediated by secreted Exo67Mackie A.R. Klyachko E. Thorne T. Schultz K.M. Millay M. Ito A. Kamide C.E. Liu T. Gupta R. Sahoo S. et al.Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction.Circ. Res. 2012; 111: 312-321Crossref PubMed Scopus (143) Google ScholarBody Fluid- or Somatic Cell-Derived ExosomesRat CMs; ischemia-mimetic conditionsmouse, acute MImiR-222 and miR-143improved neovascularization36Ribeiro-Rodrigues T.M. Laundos T.L. Pereira-Carvalho R. Batista-Almeida D. Pereira R. Coelho-Santos V. Silva A.P. Fernandes R. Zuzarte M. Enguita F.J. et al.Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis.Cardiovasc. Res. 2017; 113: 1338-1350Crossref PubMed Scopus (130) Google ScholarRat plasma, RIC-treated rat plasmaRat, I/R injuryHSP70 (stimulating TLR4 signaling and leading to the activation of ERK1/2, p38MAPK, and subsequent HSP27 phosphorylation in CMs)decreased infarct size33Vicencio J.M. Yellon D.M. Sivaraman V. Das D. Boi-Doku C. Arjun S. Zheng Y. Riquelme J.A. Kearney J. Sharma V. et al.Plasma exosomes protect the myocardium from ischemia-reperfusion injury.J. Am. Coll. Cardiol. 2015; 65: 1525-1536Crossref PubMed Scopus (344) Google ScholarHuman pericardial fluidmouse, LIlet-7b-5p (inhibiting TGFBR1 gene expression in ECs)improved post-ischemic blood flow recovery and angiogenesis34Beltrami C. Besnier M. Shantikumar S. Shearn A.I. Rajakaruna C. Laftah A. Sessa F. Spinetti G. Petretto E. Angelini G.D. Emanueli C. Human pericardial fluid contains exosomes enriched with cardiovascular-expressed microRNAs and promotes therapeutic angiogenesis.Mol. Ther. 2017; 25: 679-693Abstract Full Text Full Text PDF PubMed Scopus (131) Google ScholarHuman pericardial fluid; patients with acute MImouse, acute MIclusterinstimulated survival and neoangiogenesis, improved cardiac function, promoted the formation of CPCs; note: a shotgun proteomics analysis identified clusterin in Exo isolated from PFMI, clusterin was administered in the pericardial sac of infarcted murine hearts68Foglio E. Puddighinu G. Fasanaro P. D'Arcangelo D. Perrone G.A. Mocini D. Campanella C. Coppola L. Logozzi M. Azzarito T. et al.Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis.Int. J. Cardiol. 2015; 197: 333-347Abstract Full Text Full Text PDF PubMed Scopus (59) Google ScholarBM-MSC, bone marrow mesenchymal stem cell; CDC, cardiosphere-derived cell; CM, cardiomyocyte; CMI, convalescent myocardial infarction; CPC, cardiac progenitor cell; EC, endothelial cell; EnMSC, endometrium mesenchymal stem cell; ESC, embryonic stem cell; Exo, exosomes; IC, intracoronary; IM, intramyocardial; iPSC, induced pluripotent stem cell; I/R, ischemia/reperfusion; LI, limb ischemia; LV, left ventricle; MI, myocardial infarction; PBMC, peripheral blood mononuclear cell; PFMI, pericardial fluid from patients with acute MI; RIC, remote ischemic pre-conditioning; Shh, sonic hedgehog; UC-MSC, umbilical cord mesenchymal stem cell. Open table in a new tab BM-MSC, bone marrow mesenchymal stem cell; CDC, cardiosphere-derived cell; CM, cardiomyocyte; CMI, convalescent myocardial infarction; CPC, cardiac progenitor cell; EC, endothelial cell; EnMSC, endometrium mesenchymal stem cell; ESC, embryonic stem cell; Exo, exosomes; IC, intracoronary; IM, intramyocardial; iPSC, induced pluripotent stem cell; I/R, ischemia/reperfusion; LI, limb ischemia; LV, left ventricle; MI, myocardial infarction; PBMC, peripheral blood mononuclear cell; PFMI, pericardial fluid from patients with acute MI; RIC, remote ischemic pre-conditioning; Shh, sonic hedgehog; UC-MSC, umbilical cord mesenchymal stem cell. Cell types extensively studied for cardiac repair in experimental models and in clinical trials include embryonic stem cells (ESCs), iPSCs, and multipotent/unipotent adult stem cell lineages such as mesenchymal stem cells (MSCs), CSCs, including cardiosphere-derived cells (CDCs), and EPCs (Figure 1). Pluripotent stem cells (PSCs) have the potential for directed differentiation into all types of body cells and subsequent repair of multiple tissues, and therefore have been intensively investigated as a potential cardiac regenerative therapy. In this regard, Adamiak et al.14Adamiak M. Cheng G. Bobis-Wozowicz S. Zhao L. Kedracka-Krok S. Samanta A. Karnas E. Xuan Y.T. Skupien-Rabian B. Chen X. et al.Induced pluripotent stem cell (iPSC)-derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs.Circ. Res. 2018; 122: 296-309Crossref PubMed Scopus (155) Google Scholar recently demonstrated that EVs derived from murine iPSCs (miPSC-EVs) confer cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. These beneficial effects of miPSC-EVs may be related to their molecular cargo, which includes numerous miRNAs (e.g., miRNAs from the miR-17-92 cluster) and proteins (e.g., bone morphogenetic protein 4 [BMP4], platelet-derived growth factor alpha [PDGFA], teratocarcinoma-derived growth factor 1 [TDGF1], thrombospondin 1 [THBS1], and vascular endothelial growth factor C [VEGFC]) that have been implicated in cytoprotection and angiogenesis.14Adamiak M. Cheng G. Bobis-Wozowicz S. Zhao L. Kedracka-Krok S. Samanta A. Karnas E. Xuan Y.T. Skupien-Rabian B. Chen X. et al.Induced pluripotent stem cell (iPSC)-derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs.Circ. Res. 2018; 122: 296-309Crossref PubMed Scopus (155) Google Scholar Previously, Khan et al.15Khan M. Nickoloff E. Abramova T. Johnson J. Verma S.K. Krishnamurthy P. Mackie A.R. Vaughan E. Garikipati V.N. Benedict C. et al.Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction.Circ. Res. 2015; 117: 52-64Crossref PubMed Scopus (492) Google Scholar presented results showing that mouse ESC-derived exosomes are able to promote endogenous repair and preserve cardiac function when injected intramyocardially immediately after left anterior descending ligation in a murine model of infarction. The authors concluded that the beneficial effects observed with ESC-derived exosomes are mediated, at least in part, by the transfer of exosomal miR-294. Accumulating clinical and experimental evidence indicates that multipotent MSCs, which are capable of giving rise to cells of multiple cell lineages, are a promising cell type in the treatment of cardiac dysfunction. More recently, MSC-derived exosomes are being extensively examined for their role in MSC-based cellular therapy aimed at rebuilding damaged heart. The results of Wang and colleagues16Wang K. Jiang Z. Webster K.A. Chen J. Hu H. Zhou Y. Zhao J. Wang L. Wang Y. Zhong Z. et al.Enhanced cardioprotection by human endometrium mesenchymal stem cells driven by exosomal microRNA-21.Stem Cells Transl. Med. 2017; 6: 209-222Crossref PubMed Scopus (180) Google Scholar confirmed the superior cardioprotection, including cell survival and angiogenesis, by human endometrium-derived MSCs (EnMSC). This study identified miRNAs contained in EnMSC-derived exosomes, in particular miR-21, as potential mediators of EnMSC therapy. Ma et al.17Ma J. Zhao Y. Sun L. Sun X. Zhao X. Sun X. Qian H. Xu W. Zhu W. Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D.Stem Cells Transl. Med. 2017; 6: 51-59Crossref PubMed Scopus (204) Google Scholar isolated exosomes from Akt-overexpressing human umbilical cord MSCs and showed that they improve cardiac regeneration and promote angiogenesis through PDGFD activation. Furthermore, it was also demonstrated that the ability of exosomes obtained from mouse bone marrow-derived MSCs to repair infarcted myocardium is enhanced when cells are exposed to hypoxia.18Zhu J. Lu K. Zhang N. Zhao Y. Ma Q. Shen J. Lin Y. Xiang P. Tang Y. Hu X. et al.Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way.Artif. Cells Nanomed. Biotechnol. 2017; (Published online November 16, 2017)https://doi.org/10.1080/21691401.2017.1388249Crossref Scopus (138) Google Scholar Cardioprotective actions of exosomes in these experiments were attributed to miR-210 and neutral sphingomyelinase 2 (nSMase2) activities in hypoxia-treated MSCs and their secreted exosomes.18Zhu J. Lu K. Zhang N. Zhao Y. Ma Q. Shen J. Lin Y. Xiang P. Tang Y. Hu X. et al.Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way.Artif. Cells Nanomed. Biotechnol. 2017; (Published online November 16, 2017)https://doi.org/10.1080/21691401.2017.1388249Crossref Scopus (138) Google Scholar Because of the clinical success with MSC therapies for cardiac repair, exosomes derived from other adult stem cells have also become subjects of great attention. Specifically, CPC-derived exosomes are gaining significant attention for the clinical treatment of heart disease due to their remarkable ability to induce ischemic tissue repair and regeneration. Given their cardiac developmental origins, these endogenous cells may represent better candidates for cardiac cell therapy compared with stem cells from other sources such as adipose tissue or bone marrow. Several CPC populations have been reported in the developing and adult heart including CDCs, which can differentiate into three major cell types present in the heart: cardiomyocytes, endothelial cells, and smooth muscle cells.19Le T. Chong J. Cardiac progenitor cells for heart repair.Cell Death Discov. 2016; 2: 16052Crossref PubMed Scopus (83) Google Scholar, 20Messina E. De Angelis L. Frati G. Morrone S. Chimenti S. Fiordaliso F. Salio M. Battaglia M. Latronico M.V. Coletta M. et al.Isolation and expansion of adult cardiac stem cells from human and murine heart.Circ. Res. 2004; 95: 911-921Crossref PubMed Scopus (1226) Google Scholar CDCs are intrinsic to the heart, express a distinctive profile of antigens (>98% CD105+, <0.5% CD45+), and trigger functional recovery and structural improvements in various ischemic and nonischemic models of heart failure.21Cheng K. Malliaras K. Smith R.R. Shen D. Sun B. Blusztajn A. Xie Y. Ibrahim A. Aminzadeh M.A. Liu W. et al.Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair.JACC Heart Fail. 2014; 2: 49-61Crossref PubMed Scopus (94) Google Scholar In the previous work by Tseliou and colleagues,22Tseliou E. Fouad J. Reich H. Slipczuk L. de Couto G. Aminzadeh M. Middleton R. Valle J. Weixin L. Marbán E. Fibroblasts rendered antifibrotic, antiapoptotic, and angiogenic by priming with cardiosphere-derived extracellular membrane vesicles.J. Am. Coll. Cardiol. 2015; 66: 599-611Crossref PubMed Scopus (98) Google Scholar CDC-derived exosomes were shown to convert inert dermal fibroblasts into therapeutically active cells capable of reducing scar size and boosting cardiac function in a chronic myocardial infarction model. Exosomes have again been identified as key mediators of regenerative and functional effects caused by CDC transplantation into injured mouse hearts, especially by the direct transfer of exosomal miR-146a into recipient cells.23Ibrahim A.G. Cheng K. Marbán E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy.Stem Cell Reports. 2014; 2: 606-619Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar Recently, CDC-derived exosomes isolated by filtration and precipitation were injected into the myocardium of pigs following ischemia and reperfusion, which reduced infarct size and improved cardiac function 4 weeks later.24Gallet R. Dawkins J. Valle J. Simsolo E. de Couto G. Middleton R. Tseliou E. Luthringer D. Kreke M. Smith R.R. et al.Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction.Eur. Heart J. 2017; 38: 201-211PubMed Google Scholar As one of the very first CPC populations identified in the adult mammalian heart,25Beltrami A.P. Barlucchi L. Torella D. Baker M. Limana F. Chimenti S. Kasahara H. Rota M. Musso E. Urbanek K. et al.Adult cardiac stem cells are multipotent and support myocardial regeneration.Cell. 2003; 114: 763-776Abstract Full Text Full Text PDF PubMed Scopus (2992) Google Scholar c-Kit+ stem cells have already been employed in a phase I clinical trial for the treatment of heart failure.26Bolli R. Chugh A.R. D'Amario D. Loughran J.H. Stoddard M.F. Ikram S. Beache G.M. Wagner S.G. Leri A. Hosoda T. et al.Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.Lancet. 2011; 378: 1847-1857Abstract Full Text PDF PubMed Scopus (1107) Google Scholar Despite clinical evidence that autologous c-Kit+ adult CSCs function to improve cardiac performance, their role in the myocardial repair continues to be questioned.27Sultana N. Z