Tbx20 Induction Promotes Zebrafish Heart Regeneration by Inducing Cardiomyocyte Dedifferentiation and Endocardial Expansion
Tbx20 Induction Promotes Zebrafish Heart Regeneration by Inducing Cardiomyocyte Dedifferentiation and Endocardial Expansion
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Tbx20 诱导通过诱导心肌细胞去分化和心内膜扩张促进斑马鱼心脏再生
DOI：
10.3389/fcell.2020.00738
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发表时间：
2020-08-04
影响因子：
5.5
通讯作者：
Zhong, Tao P.
中科院分区：
文献类型：
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作者：
Fang, Yabo;Lai, Kaa Seng;Zhong, Tao P.
心脏再生需要补充丢失的心肌细胞（CM）和内膜细胞。然而，在心脏再生过程中，心肌去分化和内皮细胞激活的信号调节和转录控制还不完全清楚。在这里，我们报告说，T-Box转录因子20（Tbx 20）是诱导迅速在心肌伤口边缘响应于各种来源的心脏损伤在斑马鱼。在成人心肌中特异性诱导Tbx 20通过CM去分化促进损伤诱导的CM增殖，导致CM细胞接触的丧失和心脏胚胎或胎儿基因程序的重新表达。出乎意料的是，我们发现心肌Tbx 20诱导激活了损伤部位的心内膜，增强了心内膜细胞的延伸和增殖，从而诱导了心内膜骨形态发生蛋白6（Bmp 6）信号传导。药理学上灭活内皮细胞Bmp 6信号转导减少了其靶点Id 1和Id 2b的表达，减弱了tbx 20过表达心脏中增加的内皮细胞再生。总之，我们的研究表明，Tbx 20诱导通过诱导心肌细胞去分化以及非细胞自主增强内皮细胞再生来促进成人心脏再生。
Heart regeneration requires replenishment of lost cardiomyocytes (CMs) and cells of the endocardial lining. However, the signaling regulation and transcriptional control of myocardial dedifferentiation and endocardial activation are incompletely understood during cardiac regeneration. Here, we report that T-Box Transcription Factor 20 (Tbx20) is induced rapidly in the myocardial wound edge in response to various sources of cardiac damages in zebrafish. Inducing Tbx20 specifically in the adult myocardium promotes injury-induced CM proliferation through CM dedifferentiation, leading to loss of CM cellular contacts and re-expression of cardiac embryonic or fetal gene programs. Unexpectedly, we identify that myocardial Tbx20 induction activates the endocardium at the injury site with enhanced endocardial cell extension and proliferation, where it induces the endocardial Bone morphogenetic protein 6 (Bmp6) signaling. Pharmacologically inactivating endocardial Bmp6 signaling reduces expression of its targets, Id1 and Id2b, attenuating the increased endocardial regeneration in tbx20-overexpressing hearts. Altogether, our study demonstrates that Tbx20 induction promotes adult heart regeneration by inducing cardiomyocyte dedifferentiation as well as non-cell-autonomously enhancing endocardial cell regeneration.