Abstract 202: Low Mitochondrial Membrane Potential Identified a Novel Population of Human Cardiac Progenitor Cells with the Capacity for Myocardial Repair

As resident cardiac stem/progenitor cells (CPCs) stay in the hypoxia niche, have less metabolic activity and lower mitochondrial membrane potential, the aim of this study was to characterize a new subset of CPCs with lower mitochondrial membrane potential and examine their potential for myocardial repair. Following the live cell staining with a lipophilic cationic dye tetramethylrhodamine methyl ester (TMRM) at a final concentration of 25 nm, a novel subset of hCPCs with the lowest ~3% TMRM fluorescence were sorted from right atrial appendage derived cells (RAACs) in patients with cardiomyopathy, and named as ΔΨ m low -hCPCs, which are self-renewable, and characterized as positive (>90%) for CD90, CD44, CD140b, CD172a, however, negative (<5%) for CD34, CD45, CD54, CD117, CD133. The increased expression of pluripotent genes (LIN28, NANOG, & OCT3/4) and cardiac lineage genes (GATA4, MEF2C, MYOCD, & NKX2.5), as well as the decreased expression of cell cycle inhibitor (CDKN2A & CDKN1A) were observed in ΔΨ m low -hCPCs comparing with the non-sorted RAACs. Interestingly, ΔΨ m low -hCPCs exclusively express heme oxygenase-1 (HO-1). And CPCs positive for HO-1 and NKX2.5/GATA4 were found in the intact human heart tissue sections. ΔΨ m low -hCPCs are able to differentiate into all three cardiac lineage cells in both in vitro and in vivo conditions, and display superior ability for survival, proliferation and release of cytoprotective cytokines compared to the RAACs. At 35 days, compared with the vehicle and control cell groups, transplantation of ΔΨ m low -hCPCs significantly improve the cardiac structure and function following myocardial infarction in the immunodeficient mouse model, as indicated by the increased left ventricular (LV) ejection fraction, increased positive and negative LV dP/dt, reduced LV remodeling, and reduced infarct size. The immunohistochemistry studies showed the significant increased cardiac proliferation, newly formed cardiomyocytes, angiogenesis, and decreased cell apoptosis in the ΔΨ m low -hCPCs treated group. In summary, we identified a new hCPC population that might represent a primitive progenitor cell population within human hearts. The existence of these cells opens new opportunities for myocardial repair.