Yi Na, Wang Han-Rui, Zhu Yu-Ping, Xiao Tao, Lin Qin, Liu Huan, Meng Yi-Lei, Sun Yi-Zhuo, Lin Fang, Hu Sang-Yu, Cao Hua-Ming, Zhang Jun-Fang, Peng Lu-Ying, Li Li
State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
Shanghai Arrhythmias Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Stem Cell Res Ther. 2025 Mar 18;16(1):144. doi: 10.1186/s13287-025-04269-7.
RNA-binding proteins (RBPs) are essential in cardiac development. However, a large of them have not been characterized during the process.
We applied the human embryonic stem cells (hESCs) differentiated into cardiomyocytes model and constructed SAMD4A-knockdown/overexpression hESCs to investigate the role of SAMD4A in cardiomyocyte lineage specification.
SAMD4A, an RBP, exhibits increased expression during early heart development. Suppression of SAMD4A inhibits the proliferation of hESCs, impedes cardiac mesoderm differentiation, and impairs the function of hESC-derived cardiomyocytes. Correspondingly, forced expression of SAMD4A enhances proliferation and promotes cardiomyogenesis. Mechanistically, SAMD4A specifically binds to FGF2 via a specific CNGG/CNGGN motif, stabilizing its mRNA and enhancing translation, thereby upregulating FGF2 expression, which subsequently modulates the AKT signaling pathway and regulates cardiomyocyte lineage differentiation. Additionally, supplementation of FGF2 can rescue the proliferation defect of hESCs in the absence of SAMD4A.
Our study demonstrates that SAMD4A orchestrates cardiomyocyte lineage commitment through the post-transcriptional regulation of FGF2 and modulation of AKT signaling. These findings not only underscore the essential role of SAMD4A in cardiac organogenesis, but also provide critical insights into the molecular mechanisms underlying heart development, thereby informing potential therapeutic strategies for congenital heart disease.
RNA结合蛋白（RBPs）在心脏发育过程中至关重要。然而，其中很大一部分在这一过程中尚未得到表征。
我们应用分化为心肌细胞的人类胚胎干细胞（hESCs）模型，并构建了SAMD4A基因敲低/过表达的hESCs，以研究SAMD4A在心肌细胞谱系特化中的作用。
RBP SAMD4A在心脏早期发育过程中表达增加。抑制SAMD4A会抑制hESCs的增殖，阻碍心脏中胚层分化，并损害hESC来源的心肌细胞的功能。相应地，强制表达SAMD4A可增强增殖并促进心肌生成。机制上，SAMD4A通过特定的CNGG/CNGGN基序与FGF2特异性结合，稳定其mRNA并增强翻译，从而上调FGF2表达，进而调节AKT信号通路并调控心肌细胞谱系分化。此外，补充FGF2可以挽救缺乏SAMD4A时hESCs的增殖缺陷。
我们的研究表明，SAMD4A通过对FGF2的转录后调控和对AKT信号的调节来协调心肌细胞谱系的定向分化。这些发现不仅强调了SAMD4A在心脏器官发生中的重要作用，还为心脏发育的分子机制提供了关键见解，从而为先天性心脏病的潜在治疗策略提供了依据。
