Chen Shuo, Liang Jinxiu, Yin Jie, Zhang Weijia, Jiang Peijun, Wang Wenyuan, Chen Xiaoying, Zhou Yuanhong, Xia Peng, Yang Fan, Gu Ying, Zhang Ruilin, Han Peidong
Department of Cardiology, Center for Genetic Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
Division of Medical Genetics and Genomics, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Elife. 2025 Jul 24;13:RP101151. doi: 10.7554/eLife.101151.
Biomechanical cues play an essential role in sculpting organ formation. Comprehending how cardiac cells perceive and respond to biomechanical forces is a biological process with significant medical implications that remains poorly understood. Here, we show that biomechanical forces activate endocardial (inhibitor of DNA-binding 2b) expression, thereby promoting cardiac contractility and valve formation in zebrafish. Taking advantage of the unique strengths of zebrafish, particularly the viability of embryos lacking heartbeats, we systematically compared the transcriptomes of hearts with impaired contractility to those of control hearts. This comparison identified as a gene sensitive to blood flow. By generating a knock-in reporter line, our results unveiled the presence of in the endocardium, and its expression is sensitive to both pharmacological and genetic perturbations of contraction. Furthermore, loss-of-function resulted in progressive heart malformation and early lethality. Combining RNA-seq analysis, electrophysiology, calcium imaging, and echocardiography, we discovered profound impairment in atrioventricular (AV) valve formation and defective excitation-contraction coupling in mutants. Mechanistically, deletion of reduced AV endocardial cell proliferation and led to a progressive increase in retrograde blood flow. In the myocardium, directly interacted with the bHLH component (transcription factor 3b) to restrict its activity. Inactivating unleashed its inhibition on , resulting in enhanced repressor activity of , which subsequently suppressed the expression of (neuregulin 1), an essential mitogen for heart development. Overall, our findings identify as an endocardial cell-specific, biomechanical signaling-sensitive gene, which mediates intercellular communications between endocardium and myocardium to sculpt heart morphogenesis and function.
生物力学信号在塑造器官形成过程中起着至关重要的作用。了解心脏细胞如何感知和响应生物力学力是一个具有重大医学意义的生物学过程，但目前仍知之甚少。在此，我们表明生物力学力激活心内膜（DNA结合抑制因子2b）的表达，从而促进斑马鱼的心脏收缩力和瓣膜形成。利用斑马鱼的独特优势，特别是缺乏心跳的胚胎的生存能力，我们系统地比较了收缩力受损的心脏与对照心脏的转录组。这种比较确定了一个对血流敏感的基因。通过生成一个敲入报告基因系，我们的结果揭示了该基因在心内膜中的存在，并且其表达对收缩的药理学和基因扰动均敏感。此外，该基因功能丧失导致进行性心脏畸形和早期致死率。结合RNA测序分析、电生理学、钙成像和超声心动图，我们发现该基因突变体的房室（AV）瓣膜形成存在严重缺陷，兴奋-收缩偶联存在缺陷。从机制上讲，该基因的缺失减少了AV心内膜细胞增殖，并导致逆行血流逐渐增加。在心肌中，该基因直接与bHLH成分（转录因子3b）相互作用以限制其活性。使该基因失活解除了其对另一个基因的抑制作用，导致该基因的抑制活性增强，随后抑制了（神经调节蛋白1）的表达，神经调节蛋白1是心脏发育必需的促有丝分裂原。总体而言，我们的研究结果确定该基因为心内膜细胞特异性、生物力学信号敏感基因，其介导心内膜与心肌之间的细胞间通讯以塑造心脏形态发生和功能。
