Abstract 16932: Embryonic Stem Cell Derived Exosomes Revive Endogenous Repair Mechanisms in Failing Hearts
Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to ethical concerns, lack of autologous donors and teratoma formation. Recently, it has been observed that beneficial effects of stem cells are mediated by exosomes secreted under various physiological conditions. 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 exosomes in augmenting endogenous cardiac repair mechanisms in the heart following myocardial infarction.
Methods and Results: Exosomes were isolated from mouse ESCs (mES Ex) or embryonic fibroblasts (MEFs) by ultracentrifugation and verified by Flotillin-1 immunoblot analysis. Induction of pluripotent markers, survival and in vitro tube formation was enhanced in target cells receiving ESC exosomes. Cardiac therapeutic potential of ESC exosomes was assessed in a mouse model for myocardial infarction. Enhanced neovascularization, reduced apoptosis and fibrosis was consistent with resurgence of cardiac proliferative response in hearts receiving mES Ex compared to MEF Ex and saline treated animals at 4 weeks post infarction. Importantly, enhanced cardiac progenitor cell (CPC) survival, proliferation and cardiac commitment in vitro concurrent with increased CPCs numbers in vivo 4 weeks after mES Ex transfer. miRNA Array of ESC and MEF exosomes revealed significant enrichment of miR290-295 cluster and particularly miR-294 in ESC exosomes. Beneficial effect of mES Ex was tied to delivery of ESC specific miR-294 to the heart and in particular CPCs thereby promoting CPC survival and proliferation as analyzed by FACS cell death and CyQuant assay respectively. Enhanced G1/S transition was observed in CPCs treated with miR-294 in conjunction with significant reduction of G1 phase. Enhanced mRNA levels of cyclins A2 and E1 were observed in CPCs as well as in neonatal rat cardiomyocytes.
Conclusion: mES Ex provide a novel cell free system that utilizes the immense regenerative power of the ES cells while avoiding the risks associated with ESC research. Furthermore, ESC exosomes possess cardiac regeneration ability and modulate both cardiomyocyte and CPC based repair programs in the heart.
Author Disclosures: M. Khan: None. S.K. Verma: None. A.R. Mackie: None. P. Krishnamurthy: None. E. Vaughan: None. V.N. Garikipati: None. V. Ramirez: None. E. Lambers: None. T. Abramova: None. A. Ito: None. S. Misener: None. G. Qin: None. W.J. Koch: None. R. Kishore: None.
- © 2014 by American Heart Association, Inc.