Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2025-07-16 DOI:10.1186/s12964-025-02350-5

Man Yee Cheung, Chunmei Jiang, Imtiaz Ul Hassan, Hui Wang, Donghao Guo, Daniel Wuyang Dio, Huan Yan, Jianmin Sun, Xufeng Qi, Dongqing Cai, Wei Ge, Sheue-Yann Cheng, Wai-Yee Chan, Hui Zhao

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引用次数: 0

Abstract

Background: Thyroid hormone (TH) signaling drives cardiomyocyte (CM) maturation in endothermic animals. Elevated TH levels, coupled with increased basal metabolism, promote CM cell cycle exit and polyploidization, thus limiting heart regenerative potential. However, a comprehensive understanding of TH and its receptors, thyroid hormone receptors (TRs), orchestrating with other regulatory processes for heart regeneration, such as the hypoxia signaling pathway and post-injury metabolic switches, remains elusive.

Results: Here, we investigated the molecular mechanisms of TH signaling in heart regeneration using a time-course sequencing experiment. We assessed heart regeneration capacity in thyroid hormone receptor alpha a (thraa) mutant zebrafish, which carry an 8-bp insertion that leads to truncation of the Thraa protein and impaired TH signaling. The thraa + 8 bp mutant zebrafish exhibited an enhanced heart regenerative response. Our study showed that, in thraa^+/- mutants, a transiently augmented inflammatory response and an extended CM proliferative window are associated with metabolic switches across different phases. Moreover, we found that thraa transcriptionally regulates hypoxia-inducible factor 3 subunit alpha (hif3a), and its knockout in zebrafish impairs heart regeneration.

Conclusions: In conclusion, our study highlights the role of TH signaling via thraa in modulating zebrafish heart regeneration through metabolic regulation, inflammation, cardiac tissue regeneration, and its interplay with hif3a.

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敲除甲状腺激素受体α a （thraa）通过代谢和缺氧调节促进斑马鱼心脏再生。

背景：在吸热动物中，甲状腺激素（TH）信号驱动心肌细胞（CM）成熟。TH水平升高，加上基础代谢增加，促进CM细胞周期退出和多倍体化，从而限制心脏再生潜力。然而，对甲状腺激素及其受体甲状腺激素受体（TRs）与心脏再生的其他调控过程（如缺氧信号通路和损伤后代谢开关）的全面了解仍然难以捉摸。结果：本研究通过时间序列实验研究了TH信号在心脏再生中的分子机制。我们评估了甲状腺激素受体α a （thraa）突变斑马鱼的心脏再生能力，该斑马鱼携带一个8 bp的插入，导致thraa蛋白的截断和TH信号的受损。thraa + 8 bp突变斑马鱼表现出增强的心脏再生反应。我们的研究表明，在thraa+/-突变体中，短暂增强的炎症反应和延长的CM增殖窗口与不同阶段的代谢开关有关。此外，我们发现thra转录调节缺氧诱导因子3亚单位α (hif3a)，在斑马鱼中敲除它会损害心脏再生。结论：总之，我们的研究强调了tha信号通过代谢调节、炎症、心脏组织再生及其与hif3a的相互作用来调节斑马鱼心脏再生的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.