Elucidating the endocrine regulation of cardiac regeneration in vertebrates

摘要 器官再生潜力在本体论和系统发育上各不相同。而低等脊椎动物和 新生哺乳动物保持强大的心脏再生能力，成年哺乳动物通常解决 心脏损伤是通过纤维化造成的，而不是再生。然而，导致损失的潜在机制 这种看似有利的进化和发展特征仍然是个谜。哺乳动物心脏 由于心肌细胞周期退出和多倍化而失去再生能力。vbl.使用 心肌细胞倍性作为再生潜力的指标，我们筛选了23种哺乳动物和 鉴定裸鼠具有异常高的二倍体 心肌细胞百分比。我们发现心肌细胞倍性和 标准代谢，主要由甲状腺激素(TH)调节的生理参数。血清 NMRS中的TH对于哺乳动物来说是异常低的，初步证据表明核磁共振心肌细胞 可能会扩散。此外，我们还观察到抑制TH可增强小鼠心肌细胞 外源TH抑制斑马鱼心肌细胞增殖并降低倍性。 因此，我们假设NMRS具有增强的心脏再生潜力，并且不同的 NMRS、小鼠和斑马鱼体内的TH水平有助于它们独特的心脏再生 潜力。我们的目标#1将评估体外和体内的核磁共振心脏再生潜力。目标 #2将确定抑制TH是否能增强成年小鼠的心脏再生。Aim#3将测试 外源TH抑制斑马鱼心脏再生。TH对心脏功能影响的研究 再生可以为器官再生潜力的分子控制提供新的见解 发展和演变。

ABSTRACT 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.