2018•CirculationRequires access
Abstract 17203: Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes Salvage the Injured Myocardium by Modulation of Autophagy
Michelle Rai Santoso, Yuko Tada, Gentaro Ikeda, Ji‐Hye Jung, Evgeniya A. Vaskova, Raymond G. Sierra, Cornelius Gati, Andrew Brooks Goldstone, Daniel von Bornstaedt, Praveen Shukla, Joseph C. Wu, Soichi Wakatsuki, Joseph Yam Ting Woo, Phillip Chung-Ming Yang
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Abstract
Background: Induced pluripotent stem cells (iPSCs) and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for myocardial injury (MI). Our previous work showed that the iCMs restore the injured murine myocardium through secretion of paracrine factors, modulating apoptotic pathways to restore the murine peri-infarct region (PIR). Hypothesis: iCM-derived exosomes (iCM-Ex), a major constituent of the iCM secretome, may salvage the injured cardiomyocytes in the PIR. Methods: iCM-Ex were precipitated from iCM supernatant and characterized using various molecular analyses. Immunodeficient mice sustained MIs and received iCMs, iCM-Ex, or PBS control via direct intramyocardial injection into the PIR. Cardiac MRI assessed LV ejection fraction (LVEF) and viability at 2- and 4-week post-injection. iCMs, iCM-Ex, and PIR tissue were isolated for molecular and histological analyses. Results: iCM-Ex measured approximately 142 nm and expressed CD63 and CD9. iCM and iCM-Ex miRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. In vitro iCM apoptosis was increased significantly by hypoxia and exosome biogenesis inhibition while iCM-Ex or rapamycin reduced iCM apoptosis (p<0.05, vs. control). Mice treated with iCMs or iCM-Ex had significantly improved LVEF and LV viability compared to the control (p<0.05). Apoptosis and fibrosis were significantly reduced in iCM- and iCM-Ex treated mice. Autophagy and associated mTOR signaling pathway were significantly enhanced in iCM-Ex treatment group. Conclusions: iCM-Ex demonstrated similar efficacy as the iCMs in improving post-MI cardiac function by regulating autophagy and apoptosis of hypoxia injured cardiomyocytes. This finding represents the potential of cell-free, patient-specific biologic to treat ischemic cardiomyopathy by stimulation of an endogenous repair mechanism.