Abstract 25: P2Y14 Purinergic Receptor Overexpression: Letting Blind Cardiac Progenitor Cells ’See’ Again

Abstract

Heart failure (HF) is a leading cause of death due to limited regenerative capacity of adult mammalian heart following injury. Autologous stem cell therapy holds promise for promoting cardiac regeneration. However, stem cells derived from aged/diseased organs exhibit poor growth and survival capabilities. Empowering cardiac progenitor cells (CPC) with prosurvival genes has been attempted. Nonetheless, the molecular mechanisms by which stem cells initially detect stress signals to stimulate appropriate regenerative responses are poorly understood. This study aims to explore the physiological responses mediated by purinergic receptors, which represent a major detector for extracellular nucleotides released during injury/stress, with a focus on P2Y 14 nucleotide receptor (P2Y 14 R) activated by extracellular UDP-conjugated sugars. P2Y 14 R mediates proliferation of keratinocytes and chemotaxis of neutrophils and hematopoietic stem cells (HSCs). In addition, P2Y 14 R enhances HSC resistance to stress-induced senescence and maintains regenerative capacity after injury. However, the physiological roles of P2Y 14 R in CPCs are largely unknown. Preliminary data show striking correlations between P2Y 14 R expression in human CPCs derived from HF patients (hCPCs) and patients’ ejection fraction (EF), where low EF corresponds to low P2Y 14 R expression hCPCs. Moreover, hCPCs with relatively slower growth kinetics and enhanced senescence exhibit dramatic decreases in P2Y 14 R expression compared to fast-growing hCPCs. P2Y 14 R overexpression improves hCPC proliferation, migration, survival under stress stimuli and reverses senescent-associated phenotypes. Furthermore, P2Y 14 R-overexpressing hCPCs show remarkable upregulation in the expression of paracrine factors critical for cardiac repair. Preliminary studies will be extended in vivo to assess whether P2Y 14 R overexpression in hCPCs improves their reparative potential for injured mouse myocardium. Overall, this study introduces a novel interventional molecular approach to improve the therapeutic outcome of hCPCs by enhancing their capability to detect stress-induced extracellular nucleotides and initiate proper regenerative responses through augmenting P2Y 14 R expression.