CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS) CAS, Shanghai, 200031, China.
Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
Acta Pharmacol Sin. 2020 Dec;41(12):1576-1586. doi: 10.1038/s41401-020-00528-w. Epub 2020 Oct 9.
Type 2 inositol 1,4,5-trisphosphate receptor (IPR2) regulates the intracellular Ca release from endoplasmic reticulum in human embryonic stem cells (hESCs), cardiovascular progenitor cells (CVPCs), and mammalian cardiomyocytes. However, the role of IPR2 in human cardiac development is unknown and its function in mammalian cardiomyocytes is controversial. hESC-derived cardiomyocytes have unique merits in disease modeling, cell therapy, and drug screening. Therefore, understanding the role of IPR2 in the generation and function of human cardiomyocytes would be valuable for the application of hESC-derived cardiomyocytes. In the current study, we investigated the role of IPR2 in the differentiation of hESCs to cardiomyocytes and in the hESC-derived cardiomyocytes. By using IPR2 knockout (IPR2KO) hESCs, we showed that IPR2KO did not affect the self-renewal of hESCs as well as the differentiation ability of hESCs into CVPCs and cardiomyocytes. Furthermore, we demonstrated the ventricular-like myocyte characteristics of hESC-derived cardiomyocytes. Under the α-adrenergic stimulation by phenylephrine (10 μmol/L), the amplitude and maximum rate of depolarization of action potential (AP) were slightly affected in the IPR2KO hESC-derived cardiomyocytes at differentiation day 90, whereas the other parameters of APs and the Ca transients did not show significant changes compared with these in the wide-type ones. These results demonstrate that IPR2 has minimal contribution to the differentiation and function of human cardiomyocytes derived from hESCs, thus provide the new knowledge to the function of IPR2 in the generation of human cardiac lineage cells and in the early cardiomyocytes.
2 型肌醇 1,4,5-三磷酸受体（IPR2）调节人胚胎干细胞（hESC）、心血管祖细胞（CVPC）和哺乳动物心肌细胞内质网内的细胞内 Ca 释放。然而，IPR2 在人类心脏发育中的作用尚不清楚，其在哺乳动物心肌细胞中的功能存在争议。hESC 衍生的心肌细胞在疾病建模、细胞治疗和药物筛选方面具有独特的优势。因此，了解 IPR2 在人类心肌细胞生成和功能中的作用对于 hESC 衍生的心肌细胞的应用将是有价值的。在本研究中，我们研究了 IPR2 在 hESC 向心肌细胞分化以及 hESC 衍生的心肌细胞中的作用。通过使用 IPR2 敲除（IPR2KO）hESC，我们表明 IPR2KO 不影响 hESC 的自我更新以及 hESC 向 CVPC 和心肌细胞的分化能力。此外，我们证明了 hESC 衍生的心肌细胞具有心室样心肌细胞特征。在苯肾上腺素（10 μmol/L）的 α 肾上腺素能刺激下，IPR2KO hESC 衍生的心肌细胞在分化第 90 天的动作电位（AP）幅度和最大去极化率略有影响，而 AP 的其他参数和 Ca 瞬变与宽型相比没有明显变化。这些结果表明 IPR2 对 hESC 衍生的人类心肌细胞的分化和功能的贡献很小，从而为 IPR2 在人类心脏谱系细胞生成和早期心肌细胞中的功能提供了新知识。
