Abstract 23: p53 Mediates de novo Cardiomyocte Differentiation From c-kit Positive Cardiac Progenitor Cells

Abstract

The heart is arguably the least regenerative organ. Nonetheless, cardiac progenitor cells (CPCs) can readily be isolated from the adult heart. Moreover, we recently demonstrated that c-kit+ CPCs are able to generate de novo lineages of cardiomyocytes, endothelial cells and fibroblasts, albeit at low levels. In the present study, we assess if different pathophysiological stimuli could enhance cardiomyocyte lineage differentiation by CPCs. We first established that CPCs are heterogeneous in vivo and can be classified into three main populations based on the respective gene expression profiles: uncommitted, vascular and cardiogenic CPCs. Next, we show that transverse aortic constriction (TAC) surgery increased CPC derived cardiomyocytes by 3-fold, and enhanced non-cardiomyocyte lineages as well. Interestingly, anthracycline-induced cardiomyopathy increased CPC-derived cardiomyocytes by 35-fold. Immunostaining showed that doxorubicin stimulates p53 expression within CPCs and selectively enhanced CPC-derived cardiomyocyte lineage. The selective p53 inhibitor, pifithrin α, completely blocked the doxorubicin-mediated increase in de novo cardiomyocyte formation. Administration of p53 Activator III, RITA (reactivation of p53 and induction of tumor cell apoptosis), was sufficient to induce CPC-derived cardiomyocyte differentiation. These results demonstrate that anthracyclines can increase de novo cardiomyocyte differentiation from CPCs through activation of the p53 pathway. Ultimately, these findings might lead to new therapies for cardiac regeneration by inducing cardiomyocyte differentiation by endogenous CPCs.