Abstract 15163: Embryonic Stem Cell Dervied Exosomes Enhance Cardiac Progenitor Cell Reparative Response After Myocardial Infarction
Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration post myocardial infarction (MI) but are susceptible to teratoma formation. Recent studies indicate that exosomes (30-100nm) membrane bound vesicles contain intact protein, mRNA, and miRNA important for intercellular communication.
Objective: ESC derived exosomes can deliver ESC specific transcripts/miRNAs and proteins to promote CPC functions and augment myocardial repair following infarction.
Methods and Results: Exosomes were isolated from murine ESCs or embryonic fibroblasts (MEFs) by ultracentrifugation and verified by CD63 and CD81 immunoblot analysis. ESC exosomes enhanced cardiac progenitor cell (CPC) proliferation and metabolic activity evidenced by CyQuant and MTT assay respectively in conjunction with resistance to oxidative stress as assessed by FACS based cell death assay. In addition, increased tube formation was observed in human umbilical cord endothelial cells treated with ESC exosomes compared to MEF exosomes. In vivo therapeutic efficiency of ESC exosomes was assessed by administration into a myocardial infarction model. Enhanced ejection fraction (p< 0.05) and fractional shortening (p< 0.05) was observed 4 weeks after administration of ESC exosomes in comparison to MEF exosomes or saline treated animals. In addition, reduced infarct size and apoptosis was observed after treatment with ESC exosomes in conjunction with increased capillary density and enhanced cardiomyocyte cycling. Interestingly, enhanced CPC proliferation and cycling was observed concomitant with reduced apoptosis in ESC exosome treated animals compared to MEF exosomes and saline early after myocardial infarction indicating potential activation of CPC mediated myocardial repair. miRNA Array analysis of ESC and MEF exosomes revealed significantly high expression of miRNA 290-295 cluster in the ESC exosomes compared to MEF exosomes and may be responsible for increased myocardial repair response.
Conclusions: Collectively, ESC derived exosomes represent a novel cell free system capable of supporting myocardial regeneration as a consequence of increased CPC survival and proliferation thereby avoiding the risk of teratoma formation associated with ESCs.
- © 2013 by American Heart Association, Inc.