Activation of Nkx2.5 transcriptional program is required for adult myocardial repair.
Activation of Nkx2.5 transcriptional program is required for adult myocardial repair.
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DOI：
10.1038/s41467-022-30468-4
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发表时间：
2022-05-27
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
心脏发育网络与心肌再生潜能有关。然而，损伤后触发的胚胎信号尚未完全阐明。Nkx2.5是与人类先天性心脏病相关的关键转录因子，也是心脏祖细胞的最早标志物之一，因此它是一个有希望的候选者。在这里，我们表明，心脏特异性RNA测序研究揭示了在成年Nkx2.5功能丧失心肌的胚胎转录谱被破坏。nkx2.5−/−鱼表现出心室尖切断后恢复能力受损，去分化和增殖减少。复杂网络分析表明，Nkx2.5是必需的，以挑起必要的肌节解体和安装心肌细胞更新的增殖反应的蛋白水解途径。此外，Nkx2.5目标嵌入这些不同的基因调控模块协调适当的，多方面的损伤反应。总而言之，我们的研究结果支持了以前未被认识到的Nkx2.5依赖性再生回路，该回路引起心肌细胞周期重新进入，蛋白水解和线粒体代谢，以确保硬骨鱼心脏的有效再生。心脏发育基因与再生潜能有关。在这里，作者确定了一个Nkx2.5依赖的基因调控网络，通过ect 2，psmb 3和psmd 7来协调心肌修复过程中的细胞周期重新进入，蛋白水解和线粒体代谢。
The cardiac developmental network has been associated with myocardial regenerative potential. However, the embryonic signals triggered following injury have yet to be fully elucidated. Nkx2.5 is a key causative transcription factor associated with human congenital heart disease and one of the earliest markers of cardiac progenitors, thus it serves as a promising candidate. Here, we show that cardiac-specific RNA-sequencing studies reveal a disrupted embryonic transcriptional profile in the adult Nkx2.5 loss-of-function myocardium. nkx2.5−/− fish exhibit an impaired ability to recover following ventricular apex amputation with diminished dedifferentiation and proliferation. Complex network analyses illuminate that Nkx2.5 is required to provoke proteolytic pathways necessary for sarcomere disassembly and to mount a proliferative response for cardiomyocyte renewal. Moreover, Nkx2.5 targets embedded in these distinct gene regulatory modules coordinate appropriate, multi-faceted injury responses. Altogether, our findings support a previously unrecognized, Nkx2.5-dependent regenerative circuit that invokes myocardial cell cycle re-entry, proteolysis, and mitochondrial metabolism to ensure effective regeneration in the teleost heart. Cardiac developmental genes have been associated with regenerative potential. Here the authors identify a Nkx2.5-dependent gene regulatory network operating through ect2, psmb3, and psmd7 to orchestrate cell cycle re-entry, proteolysis, and mitochondrial metabolism during myocardial repair.
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