title: Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction.
abstract: BACKGROUND
  Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to various concerns. Recently, salutary effects of stem cells have been connected to exosome secretion. ESCs have the ability to produce exosomes, however, their effect in the context of the heart is unknown.
  
  
  OBJECTIVE
  Determine the effect of ESC-derived exosome for the repair of ischemic myocardium and whether c-kit(+) cardiac progenitor cells (CPCs) function can be enhanced with ESC exosomes.
  
  
  RESULTS
  This study demonstrates that mouse ESC-derived exosomes (mES Ex) possess ability to augment function in infarcted hearts. mES Ex enhanced neovascularization, cardiomyocyte survival, and reduced fibrosis post infarction consistent with resurgence of cardiac proliferative response. Importantly, mES Ex augmented CPC survival, proliferation, and cardiac commitment concurrent with increased c-kit(+) CPCs in vivo 8 weeks after in vivo transfer along with formation of bonafide new cardiomyocytes in the ischemic heart. miRNA array revealed significant enrichment of miR290-295 cluster and particularly miR-294 in ESC exosomes. The underlying basis for the beneficial effect of mES Ex was tied to delivery of ESC specific miR-294 to CPCs promoting increased survival, cell cycle progression, and proliferation.
  
  
  CONCLUSIONS
  mES Ex provide a novel cell-free system that uses the immense regenerative power of ES cells while avoiding the risks associated with direct ES or ES-derived cell transplantation and risk of teratomas. ESC exosomes possess cardiac regeneration ability and modulate both cardiomyocyte and CPC-based repair programs in the heart.
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Emily
authors.initials: E
authors.lastname: Nickoloff
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Tatiana
authors.initials: T
authors.lastname: Abramova
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnson
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Verma
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Alexander Roy
authors.initials: AR
authors.lastname: Mackie
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Erin
authors.initials: E
authors.lastname: Vaughan
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Venkata Naga Srikanth
authors.initials: VN
authors.lastname: Garikipati
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Benedict
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Veronica
authors.initials: V
authors.lastname: Ramirez
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Erin
authors.initials: E
authors.lastname: Lambers
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Aiko
authors.initials: A
authors.lastname: Ito
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Sol
authors.initials: S
authors.lastname: Misener
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Luongo
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: John
authors.initials: J
authors.lastname: Elrod
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.).
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: From the Center for Translational Medicine (M.K., E.N., J.J., S.K.V., P.K., E.V., V.N.S.G., C.B., E.G., T.L., J.E., W.J.K.), Cardiovascular Research Center (S.R.H.), Department of Physiology (S.R.H.), and Department of Pharmacology (T.L., W.J.K., R.K.), Temple University School of Medicine, Philadelphia, PA; and Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL (T.A., A.R.M., E.V., V.R., E.L., A.I., S.M., G.Q., R.K.). raj.kishore@temple.edu.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
mesh_terms: D000818:Animals; D002470:Cell Survival; D002474:Cell-Free System; D003094:Collagen; D004338:Drug Combinations; D053595:Embryonic Stem Cells / Q000502:physiology* / Q000648:ultrastructure; D055354:Exosomes / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology / Q000648:ultrastructure; D005355:Fibrosis; D018507:Gene Expression Regulation, Developmental; D006352:Heart Ventricles; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology / Q000648:ultrastructure; D007267:Injections; D007797:Laminin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D009024:Morphogenesis; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D018919:Neovascularization, Physiologic; D010101:Oxygen Consumption; D011509:Proteoglycans; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014463:Ultrasonography
chemical_list: D004338:Drug Combinations; D007797:Laminin; D035683:MicroRNAs; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen
keywords: embryonic stem cells; exosomes; microRNAs