Evolution des Régulations Endocriniennes, Département Adaptation du vivant, CNRS UMR 7221, Muséum National d'Histoire Naturelle, Sorbonne Université, 75231 Paris, France.
Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC 3052, Australia.
Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3614-3623. doi: 10.1073/pnas.1803794116. Epub 2019 Feb 12.
Despite therapeutic advances, heart failure is the major cause of morbidity and mortality worldwide, but why cardiac regenerative capacity is lost in adult humans remains an enigma. Cardiac regenerative capacity widely varies across vertebrates. Zebrafish and newt hearts regenerate throughout life. In mice, this ability is lost in the first postnatal week, a period physiologically similar to thyroid hormone (TH)-regulated metamorphosis in anuran amphibians. We thus assessed heart regeneration in before, during, and after TH-dependent metamorphosis. We found that tadpoles display efficient cardiac regeneration, but this capacity is abrogated during the metamorphic larval-to-adult switch. Therefore, we examined the consequence of TH excess and deprivation on the efficiently regenerating tadpole heart. We found that either acute TH treatment or blocking TH production before resection significantly but differentially altered gene expression and kinetics of extracellular matrix components deposition, and negatively impacted myocardial wall closure, both resulting in an impeded regenerative process. However, neither treatment significantly influenced DNA synthesis or mitosis in cardiac tissue after amputation. Overall, our data highlight an unexplored role of TH availability in modulating the cardiac regenerative outcome, and present as an alternative model to decipher the developmental switches underlying stage-dependent constraint on cardiac regeneration.
尽管治疗方法有所进步，但心力衰竭仍是全球发病率和死亡率的主要原因，但为什么成年人的心脏再生能力会丧失仍是一个谜。心脏的再生能力在脊椎动物中差异很大。斑马鱼和蝾螈的心脏可以终生再生。在小鼠中，这种能力在出生后的第一周就丧失了，这一时期在生理上与无尾两栖动物的甲状腺激素（TH）调节变态相似。因此，我们评估了在 TH 依赖性变态过程中的心脏再生。我们发现，蝌蚪表现出有效的心脏再生能力，但这种能力在变态幼虫到成年的转变过程中被削弱。因此，我们研究了 TH 过量和缺乏对有效再生的蝌蚪心脏的影响。我们发现，急性 TH 处理或在切除前阻断 TH 产生都会显著但不同地改变细胞外基质成分沉积的基因表达和动力学，并对心肌壁闭合产生负面影响，这两者都会导致再生过程受阻。然而，两种处理方法都不会显著影响心脏组织在截肢后的 DNA 合成或有丝分裂。总的来说，我们的数据强调了 TH 可用性在调节心脏再生结果方面的未知作用，并提出 作为一种替代模型来破译心脏再生的阶段性限制背后的发育开关。
