Abstract 15173: Empowering Human Cardiac Progenitor Cell-mediated Repair of Injured Myocardium by Overexpressing P2Y14 Nucleotide Receptor
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 proliferation and migration 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 in human CPCs (hCPCs) isolated from patients undergoing left ventricular assist device (LVAD) implantation surgery. The G protein-coupled UDP-sugar-sensing P2Y14 receptor (P2Y14R) has been shown to stimulate keratinocyte proliferation and migration, neutrophil and hematopoietic stem cell (HSC) chemotaxis in addition to increasing HSC resistance to stress-induced senescence. We aim to determine whether P2Y14R plays similar regenerative roles in cardiac tissue where the P2Y14R-mediated physiological responses haven’t been previously addressed. Our preliminary data show that the P2Y14R selective agonist UDP-Glucose enhances hCPC proliferation, migration and survival. Interestingly, hCPCs that exhibit relatively slower growth kinetics and enhanced senescence show a dramatic decrease in P2Y14R expression compared to fast-growing hCPCs consistent with our hypothesis that overexpressing P2Y14R participates in rejuvenating hCPCs and improving their growth capabilities. This hypothesis will be tested in vivo by determining whether P2Y14R overexpression in hCPCs improves their reparative potential for injured mouse myocardium. Mechanistically, we show for the first time that UDP-Glu induces downstream activation of YAP linking the extracellular nucleotides released during cardiac ischemia to extracellular matrix sensing and Hippo signaling that have been recently implicated in cardiac regeneration.
- Heart Failure
- Stem Cell Therapy
- Human Cardiac Progenitor Cells
- P2Y14 Nucleotide Receptor
- Hippo Signaling
Author Disclosures: F. El-Sayed: None. J. Nguyen: None. M. Sussman: Other; Significant; CardioCreate Company.
- © 2015 by American Heart Association, Inc.