UCSF

Cardiac regenerative potential varies considerably across and within vertebrate species. Heart regeneration is an ancestral trait that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures, and as members of certain species developmentally progress towards their adult forms. While lower vertebrates and neonatal mammals retain robust capacities for cardiomyocyte (CM) proliferation and cardiac regeneration, adult mammalian CMs lose proliferative potential due to cell-cycle withdrawal and polyploidization, failing to mount a proliferative response to regenerate lost myocardium after cardiac injury. The decline of murine CM proliferative potential occurs in the neonatal period when the endocrine system undergoes drastic changes for adaptation to extrauterine life. Here, we demonstrate that thyroid hormone (TH) signaling functions as a primary factor driving CM proliferative potential loss in vertebrates, able to shut down regeneration when present and enhance regeneration when absent. Furthermore, we implicate thyroid hormone as a critical driver of endothermy acquisition as well as CM cell cycle exit. We also show that agonists of glucocorticoid receptor (GR) and vitamin D receptor (VDR) suppressed neonatal CM proliferation in vitro. We examined CM nucleation and proliferation in neonatal mutant mice lacking GR or VDR specifically in CMs, but we observed no difference between mutant and control littermates. Additionally, we generated compound mutant mice that lack GR or VDR and express dominant-negative TH receptor alpha in their CMs, and similarly observed no increase in neonatal CM proliferative potential compared to dominant-negative TH receptor alpha mice alone. Thus, although GR and VDR activation in cultured neonatal CMs is sufficient to inhibit CM proliferation, they seem to be dispensable for neonatal CM cell-cycle exit and binucleation in vivo. Our results suggest distinct roles for several endocrine players in governing cardiac regenerative potential in vertebrates.