HeartCaRe

Cardiovascular diseases are the leading cause of mortality (33% of all deaths in the USA in 2008 and 29% in France). Cardiac diseases are characterized by molecular, cellular and physiological changes in the myocardium, coronary vessels and valves, resulting in cardiomyocyte deficiency and impaired cardiac function that ultimately leads to congestive heart failure. Despite significant advances, conventional treatments do not correct the defects in cardiac muscle cell numbers and the prognosis of congestive heart failure remains poor. For this reason, the replacement of lost cardiomyocytes is a primary target of regenerative medicine research. The recent discoveries of adult cardiomyocyte proliferative capacities together with the existence of resident cardiac progenitors in the adult heart have orientated cardiovascular research toward two different therapeutical strategies that aim on one side to activate adult cardiomyocyte cell cycle reentry and on the other to stimulate differentiation of endogenous cardiac progenitor cells. Although recent studies have uncovered the remarkable regenerative capacity of the newborn mammalian heart, this regenerative potential is lost shortly after birth, strongly supporting the hypothesis that a detailed understanding of developmental mechanisms is essential to identify targets for cardiac repair or regeneration in congenital and acquired heart diseases. The HeartCaRe project aims to advance these alternative but clearly complementary approaches for heart repair and regeneration by contributing to the identification of the developmental mechanisms controlling cardiomyocyte proliferation and cardiac progenitor cell fate which will lead to the identification of clinically relevant targets for heart repair. Our first objective is to identify novel regulators of fetal and adult cardiomyocyte proliferation. We recently uncovered a role for the fibroblast growth factor 10 (FGF10) signaling in regulating both fetal and adult cardiomyocyte proliferation. Here we will investigate FGF10 and its downstream signaling pathway as potential clinically relevant targets for promoting adult cardiomyocyte cell-cycle reentry after heart injury. In parallel, a transcriptome based approach will characterize regional proliferative programs in the fetal heart. The second objective of our project aims to identify the mechanisms regulating cardiac progenitor cell maintenance and differentiation. Given the similar transcriptional signature of residual stem cells and early cardiac progenitors, we hypothesize that molecular mechanisms controlling early cardiac progenitor cell fate are involved in resident stem cell maintenance and differentiation at fetal stages and in the adult heart under normal and pathological conditions. In particular, we will study role of the transcription factor HES1 that we have identified as a novel regulator of early cardiac progenitor cells. In addition, the importance of oscillatory cAMP signaling in the control of cardiac progenitor cell fate decisions, potentially acting upstream of Hes1, will be investigated during development and in pathological conditions. Using a combination of state of the art molecular, developmental, physiological and transgenic approaches including novel reporter lines, and building on promising preliminary results, the HeartCaRe project will enhance our knowledge of cardiac development and will contribute to a greater understanding of regulatory steps controlling cardiomyocyte proliferation and progenitor cell fate. Stimulation of endogenous multipotent cardiac progenitor cells together with triggering cell cycle re-entry of existing cardiomyocytes currently represent the most promising approaches for cardiac repair over the coming years. Identifying how these processes are regulated is thus of crucial importance in regenerative medicine and will inform future cardiac repair strategies.