Abstract 110: Human-Induced Pluripotent Stem Cell Derived Exosomal Protein Induce Cardiac Regeneration

Cardiovascular diseases are the leading causes of death worldwide. After myocardial infarction (MI), there is a permanent loss of cardiomyocytes (CMs), and as the mammalian heart has limited regenerative capacity, it leads to Heart Failure. Recent studies from zebrafish and 1-day old mice showed that they could regenerate their heart through inducing existing CM proliferation. Attempts have been made to transiently reconstitute embryonic signaling in adult hearts, including overexpression of cell cycle activating genes with limited success. iPSC-derived extracellular vesicles (EV)/exosomes have been shown to improve cardiac function and some degree of CM renewal. However, the iPSC-EVs-mediated cardiac regeneration mechanism remains unclear and largely pertains to microRNAs and other RNAs, with a little elucidation of the role of iPSC-exosome proteins. The myocardial delivery of iPSC-EV-specific protein improves cardiac function and remodeling post-MI by activating pro-proliferative and anti-oxidative stress molecular pathways. Our preliminary studies showed that hiPSC-EVs induced the CM cell cycle in mice post-MI, and by employing a proteomic approach, we found a novel protein exclusively expressed in iPSC-EVs. The overexpression of hiPSC-EV enriched protein in the form of modRNA (modified mRNA) induced a robust CM cell cycle in rat neonatal CMs and in adult hearts post-MI. This increase in the CMs cell cycle by the modRNA was associated with reduced scar size, improved cardiac function (%EF 49.76 ± 5.8 vs. 27.47 ± 6.9 (control, Luc modRNA), respectively), and mice survival 28 days post-MI. Furthermore, using the siRNA and modRNA (inhibition and over-expression) approach, we found that the protein-induced Yap1-β-catenin molecular pathway stimulates CM proliferation. Furthermore, the overexpression protein post-MI inhibited the CM apoptosis (TUNEL CMs, 1.3% ± 0.1 vs. 2.1% ± 0.11 (control)) by reducing oxidative stress and DNA damage response. The myocardial injection of iPSC-EV specific protein through a highly therapeutic modRNA tool improve cardiac function by inducing CMs proliferation, inhibiting oxidative stress, and reactivating cardiac regeneration post-injury.

Duke Scholars

Author Rajika Roy Surgery, Cardiovascular and Thoracic Surgery