Meng Ya, Deng Chunhao, Xiao Xia, Wei Shengnan, Song Chengcheng, Wang Jiaxian, Lei Chon Lok, Liu Weiwei, Chen Guokai
Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People's Hospital, Zhuhai Clinical Medical College of Jinan University, Zhuhai, Guangdong, 519000, China.
Faculty of Health Sciences, University of Macau, Taipa, Macau.
Int J Biol Sci. 2025 Jan 1;21(1):95-108. doi: 10.7150/ijbs.95568. eCollection 2025.
Ion channels play a crucial role in cardiac functions, and their activities exhibit dynamic changes during heart development. However, the precise function of ion channels in human heart development remains elusive. In this study, we utilized human embryonic stem cells (hESCs) as a model to mimic the process of human embryonic heart development. During hESCs differentiation into cardiomyocytes, we observed differential expression of ion channel genes, including upregulation of ryanodine receptor 2 (RYR2), which encodes a calcium release channel. Subsequently, we discovered that Suramin, an activator of RyR2, efficiently promoted cardiac differentiation even in the absence of conventional WNT inhibitors. Furthermore, various modulators targeting sodium channels, potassium channels or chloride channels were examined under chemically defined conditions during cardiac differentiation. We found that DIDS, a chloride transport inhibitor, also enhanced hESCs differentiation into cardiomyocytes. Both Suramin and DIDS partially inhibited WNT signaling pathway, and RYR2 knockdown attenuated cardiac differentiation induced by WNT inhibitor treatment, or Suramin or DIDS administration. The resulting cardiomyocytes induced by these ion modulators exhibited specific expression patterns of cardiac genes and displayed typical electrophysiological signals. Notably, compared to WNT inhibitor treatment group, both Suramin and DIDS led to increased generation of atrial-like cardiomyocytes suggesting their potential as alternative inducers for specific cardiomyocyte lineage commitment during human cardiomyocyte induction processes. This study demonstrates that regulation of ion channels plays a crucial role in determining the fate of cardiac cells, providing an effective approach for inducing cardiomyocytes from hPSCs and highlighting their critical involvement in human heart development.
离子通道在心脏功能中发挥着至关重要的作用，并且它们的活性在心脏发育过程中呈现动态变化。然而，离子通道在人类心脏发育中的精确功能仍不清楚。在本研究中，我们利用人类胚胎干细胞（hESC）作为模型来模拟人类胚胎心脏发育过程。在hESC分化为心肌细胞的过程中，我们观察到离子通道基因的差异表达，包括编码钙释放通道的兰尼碱受体2（RYR2）的上调。随后，我们发现苏拉明（Suramin），一种RyR2的激活剂，即使在没有传统WNT抑制剂的情况下也能有效促进心脏分化。此外，在心脏分化过程中，在化学限定条件下检测了各种靶向钠通道、钾通道或氯通道的调节剂。我们发现，氯转运抑制剂DIDS也增强了hESC向心肌细胞的分化。苏拉明和DIDS都部分抑制了WNT信号通路，并且RYR2基因敲低减弱了WNT抑制剂处理、或苏拉明或DIDS给药诱导的心脏分化。这些离子调节剂诱导产生的心肌细胞表现出心脏基因的特定表达模式，并显示出典型的电生理信号。值得注意的是，与WNT抑制剂处理组相比，苏拉明和DIDS都导致心房样心肌细胞的生成增加，表明它们在人类心肌细胞诱导过程中作为特定心肌细胞谱系定向的替代诱导剂的潜力。这项研究表明，离子通道的调节在决定心脏细胞命运中起着关键作用，为从hPSC诱导心肌细胞提供了一种有效方法，并突出了它们在人类心脏发育中的关键参与。
