Molecular control of cardiac regenerative potential

Project Summary/Abstract Around birth, mammals undergo the most complex and profound physiologic and metabolic changes for adaptations to the extrauterine life. Intriguingly, this process is accompanied with loss of tissue regenerative potential in many organs including the heart, skin and brain. The upstream signals that drive the perinatal loss of organ regenerative capacity are largely unknown. Our study of heart regeneration suggests that activation of thermogenic pathways such as the perinatal increase of circulating thyroid hormone levels and adrenergic receptor activity during the ectotherm-to-endotherm transition inhibits cardiomyocyte proliferative potential and heart regeneration in ontogeny and phylogeny (Hirose et al., Science 2019; Payumo et al., Circulation 2021). Following this direction, we recently made preliminary yet intriguing observations that another thermogenic pathway also regulates mammalian cardiomyocyte renewal potential. In this proposal, we will investigate whether thermogenic tissues control mammalian cardiomyocyte cell-cycle arrest after birth. Their impact on cardiomyocyte regeneration and heart repair after myocardial infarction will also be determined in adult mice. Furthermore, the signaling molecules mediating the thermogenic organ-heart crosstalk will be examined. Collectively, our proposed experiments will shed lights into the molecule mechanism and fundamental principle governing the loss of organ regenerative capacity after the acquisition of endothermy.