Abstract 159: Empowering Cardiac Progenitor Cell-mediated Repair of Injured Myocardium by Overexpressing P2Y2 Nucleotide Receptor

Abstract

Heart failure is a leading cause of death in the US due to the limited capability of adult mammalian heart to regenerate following injury. Autologous stem cell therapy holds promise for regeneration of injured myocardium after myocardial infarction. However, stem cells derived from diseased organs exhibit impaired proliferative and migratory capabilities and increased susceptibility to cell death. Empowering stem cells from diverse origins, including cardiac progenitor cells (CPCs), with pro-survival genes has been attempted. Despite the well-established roles of purinergic signaling mediated by extracellular nucleotides in regulating diverse cellular responses in cardiovascular diseases, it has not been well-defined in CPCs. Our preliminary data show, for the first time, that the majority of P2 purinergic receptors are expressed and exhibit functional responses to ATP and UTP in mouse and human CPCs. Since previous findings have shown that the G protein-coupled P2Y 2 receptor (P2Y 2 R) induces cardioprotective responses in animal models as well as human cardiomyocytes and regulates a wide range of signaling pathways that are crucial to tissue repair in various experimental models and in stem cells from diverse origins, we aim to determine whether P2Y 2 R plays similar roles in CPCs. Our preliminary data show that the P2Y 2 R agonists ATP and UTP enhance human CPC (hCPC) proliferation, migration and survival. Interestingly, hCPCs that exhibit relatively slower growth kinetics and higher levels of senescence markers show a dramatic decrease in P2Y 2 R expression as compared to fast-growing hCPCs consistent with our hypothesis that overexpressing P2Y 2 R participates in rejuvenating hCPCs and improving their growth capabilities. This hypothesis will be tested in vivo by determining whether P2Y 2 R overexpression in hCPCs improves their reparative potential for injured mouse myocardium. We also introduce the novel hypothesis that P2Y 2 R-induced regenerative responses in hCPCs involve the activation of Hippo signaling that is known to be regulated by different GPCRs, which links the extracellular nucleotides released during cardiac ischemia to extracellular matrix sensing and Hippo signaling that have been recently implicated in cardiac regeneration.