Organ regenerative potential varies ontologically and phylogenetically. While lower vertebrates and neonatal mammals retain robust capacities for heart regeneration, adult mammals generally resolve cardiac injury through fibrosis, not regeneration. However, the underlying mechanisms driving loss of such a seemingly advantageous trait in evolution and development remain enigmatic. Mammalian hearts lose regenerative potential due to cardiomyocyte cell-cycle withdrawal and polyploidization. Using cardiomyocyte ploidy as an indicator of regenerative potential, we screened 23 mammalian species and identified the Naked-Mole Rat (NMR), Heterocephalus glaber, as having an unusually high diploid cardiomyocyte percentage. We uncovered a robust correlation between cardiomyocyte ploidy and standard metabolism, a physiological parameter primarily regulated by thyroid hormone (TH). Serum TH in NMRs is unusually low for a mammal, and preliminary evidence suggests NMR cardiomyocytes can proliferate. Additionally, we have observed that TH inhibition enhances mouse cardiomyocyte proliferation and reduces ploidy, while exogenous TH inhibits cardiomyocyte proliferation in zebrafish. Thus, we hypothesize that NMRs possess enhanced cardiac regenerative potential and that the distinct TH levels in NMRs, mice, and zebrafish contribute to their distinct cardiac regenerative potentials.
Our Aim #1 will assess NMR cardiac regenerative potential in vitro and in vivo.
Aim #2 will determine if TH inhibition enhances cardiac regeneration in adult mice.
Aim #3 will test whether exogenous TH inhibits cardiac regeneration in zebrafish. Studying the influence of TH over cardiac regeneration could yield novel insights into the molecular control of organ regenerative potential in development and evolution.
Elucidating the developmental regulators that shut down cardiac regeneration potential in mammals could inspire novel therapies that enhance cardiac regeneration after ischemic injury in patients and ameliorate the effects of heart disease ? the leading cause of death in the United States.
