Identifying superior cardiac progenitor cells for treating ischemic cardiomyopathy

Stem cell therapy holds promise as a therapeutic approach to regenerate damaged myocardium. The heart contains small populations of indigenous committed cardiac progenitor cells (CPC). Recent studies show the controversy of using cell surface marker, such as c-kit, in identifying CPC. GATA4 is a cardiac-specific transcription factor that is expressed in cardiac progenitors with cardiomyogenic potential. The level of GATA4 expression varies amongst populations of stem cells, and the role of GATA4 in regulating CPC function is unknown. Using GATA4 reporter mice, we observed that CPC with high promoter activity (GATA4high) exhibit high endogenous HIF-1a; and VEGF164 protein expression and are resistant to nutrient depletion and hypoxia in vitro compared with CPC with low promoter activity (GATA4 low). Moreover, GATA4high CPC exhibit evidence of enhanced cardiomyocyte differentiation in vitro. Finally, under hypoxic conditions, GATA4high CPC release higher concentrations of key paracrine factors that may promote angiogenesis and stem cell chemotaxis. These data suggest that GATA4high CPC represent a sub-selective stem cell population that could be highly efficacious for cardiovascular repair. The proposed research is to investigate the feasibility to use GATA4, a key cardiac early transcription factor, other than cell surface marker, to isolate superior CPC for heart repair. The goal of this proposal is to directly compare GATA4 high and GATA4 low CPC with regard to cell viability, cardiovascular lineage differentiation, paracrine effects and heart protection post-transplantation using both in vitro and in vivo models. We will also investigate the role of HIF-1a; in mediating the functional differences between the two CPC populations. We expect that GATA4high CPC will exhibit enhanced survival as well as angiogenic and cardiomyogenic potential than GATA4low CPC. Overall, successful completion of these aims can help us to identify CPC sub-populations with superior efficacy for heart regeneration. These results will have important translational implications for improving cardiac progenitor cell therapy for patients with ischemic cardiomyopathy leading to congestive heart failure. (AHA Program: Grant-in-Aid)