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Original Research

Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction

Mohsin Khan, Emily Nickoloff, Tatiana Abramova, Jennifer Johnson, Suresh K Verma, Prasanna Krishnamurthy, Alexander R Mackie, Erin Vaughan, Venkata NS Garikipati, Cynthia L Benedict, Veronica Ramirez, Erin Lambers, Aiko Ito, Erhe Gao, Sol Misener, Gangjian Qin, Timothy S Luongo, John W Elrod, Steven R Houser, Walter J Koch, Raj Kishore
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https://doi.org/10.1161/CIRCRESAHA.117.305990
Circulation Research. 2015;CIRCRESAHA.115.305990
Originally published April 22, 2015
Mohsin Khan
Center for Translational Medicine, Temple University School of Medicine
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Emily Nickoloff
Center for Translational Medicine, Temple University School of Medicine
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Tatiana Abramova
Feinberg Cardiovascular Research Institute, Northwestern University
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Jennifer Johnson
Center for Translational Medicine, Temple University School of Medicine
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Suresh K Verma
Center for Translational Medicine, Temple University School of Medicine
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Prasanna Krishnamurthy
Cardiovascular Sciences, Houston Methodist Research Institute
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Alexander R Mackie
Feinberg Cardiovascular Research Institute, Northwestern University
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Erin Vaughan
Feinberg Cardiovascular Research Institute, Northwestern University
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Venkata NS Garikipati
Center for Translational Medicine, Temple University School of Medicine
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Cynthia L Benedict
Center for Translational Medicine, Temple University School of Medicine
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Veronica Ramirez
Feinberg Cardiovascular Research Institute, Northwestern University
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Erin Lambers
Feinberg Cardiovascular Research Institute, Northwestern University
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Aiko Ito
Feinberg Cardiovascular Research Institute, Northwestern University
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Erhe Gao
Center for Translational Medicine, Temple University School of Medicine
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Sol Misener
Feinberg Cardiovascular Research Institute, Northwestern University
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Gangjian Qin
Feinberg Cardiovascular Research Institute, Northwestern University
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Timothy S Luongo
Center for Translational Medicine, Temple University School of Medicine
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John W Elrod
Pharmacology, Temple University School of Medicine
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Steven R Houser
Cardiovascular Research Center, Temple University School of Medicine
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Walter J Koch
Center for Translational Medicine, Temple University School of Medicine
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Raj Kishore
Pharmacology, Temple University School of Medicine
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  • For correspondence: raj.kishore@temple.edu
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Abstract

Rationale: 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+ CPCs function can be enhanced with ESC exosomes

Methods and 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 cardiac progenitor cell (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 utilizes 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.

  • Exosomes
  • Cardiac repair
  • embryonic stem cell
  • microvesicles
  • microRNA
  • cardiac progenitor cells
  • Received January 6, 2015.
  • Revision received April 5, 2015.
  • Accepted April 22, 2015.
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    Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction
    Mohsin Khan, Emily Nickoloff, Tatiana Abramova, Jennifer Johnson, Suresh K Verma, Prasanna Krishnamurthy, Alexander R Mackie, Erin Vaughan, Venkata NS Garikipati, Cynthia L Benedict, Veronica Ramirez, Erin Lambers, Aiko Ito, Erhe Gao, Sol Misener, Gangjian Qin, Timothy S Luongo, John W Elrod, Steven R Houser, Walter J Koch and Raj Kishore
    Circulation Research. 2015;CIRCRESAHA.115.305990, originally published April 22, 2015
    https://doi.org/10.1161/CIRCRESAHA.117.305990

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    Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction
    Mohsin Khan, Emily Nickoloff, Tatiana Abramova, Jennifer Johnson, Suresh K Verma, Prasanna Krishnamurthy, Alexander R Mackie, Erin Vaughan, Venkata NS Garikipati, Cynthia L Benedict, Veronica Ramirez, Erin Lambers, Aiko Ito, Erhe Gao, Sol Misener, Gangjian Qin, Timothy S Luongo, John W Elrod, Steven R Houser, Walter J Koch and Raj Kishore
    Circulation Research. 2015;CIRCRESAHA.115.305990, originally published April 22, 2015
    https://doi.org/10.1161/CIRCRESAHA.117.305990
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