Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
J Mol Cell Biol. 2017 Aug 1;9(4):274-288. doi: 10.1093/jmcb/mjx014.
Ca2+ signals participate in various cellular processes with spatial and temporal dynamics, among which, inositol 1,4,5-trisphosphate receptors (IP3Rs)-mediated Ca2+ signals are essential for early development. However, the underlying mechanisms of IP3R-regulated cell fate decision remain largely unknown. Here we report that IP3Rs are required for the hematopoietic and cardiac fate divergence of mouse embryonic stem cells (mESCs). Deletion of IP3Rs (IP3R-tKO) reduced Flk1+/PDGFRα- hematopoietic mesoderm, c-Kit+/CD41+ hematopoietic progenitor cell population, and the colony-forming unit activity, but increased cardiac progenitor markers as well as cardiomyocytes. Concomitantly, the expression of a key regulator of hematopoiesis, Etv2, was reduced in IP3R-tKO cells, which could be rescued by the activation of Ca2+ signals and calcineurin or overexpression of constitutively active form of NFATc3. Furthermore, IP3R-tKO impaired specific targeting of Etv2 by NFATc3 via its evolutionarily conserved cis-element in differentiating ESCs. Importantly, the activation of Ca2+-calcineurin-NFAT pathway reversed the phenotype of IP3R-tKO cells. These findings reveal an unrecognized governing role of IP3Rs in hematopoietic and cardiac fate commitment via IP3Rs-Ca2+-calcineurin-NFATc3-Etv2 pathway.
钙离子信号参与具有时空动态的各种细胞过程，其中，三磷酸肌醇受体（IP3Rs）介导的钙离子信号对于早期发育至关重要。然而，IP3R 调节细胞命运决定的潜在机制在很大程度上仍不清楚。在这里，我们报告 IP3Rs 是小鼠胚胎干细胞（mESCs）造血和心脏命运分歧所必需的。IP3Rs 的缺失（IP3R-tKO）减少了 Flk1+/PDGFRα-造血中胚层、c-Kit+/CD41+造血祖细胞群体和集落形成单位活性，但增加了心脏祖细胞标志物和心肌细胞。同时，造血关键调节因子 Etv2 的表达在 IP3R-tKO 细胞中减少，这可以通过激活钙离子信号和钙调神经磷酸酶或过表达组成型激活形式的 NFATc3 来挽救。此外，IP3R-tKO 通过 NFATc3 进化保守的顺式元件破坏了 Etv2 在分化的 ESCs 中的特异性靶向。重要的是，Ca2+-钙调神经磷酸酶-NFAT 通路的激活逆转了 IP3R-tKO 细胞的表型。这些发现揭示了 IP3Rs 通过 IP3Rs-Ca2+-钙调神经磷酸酶-NFATc3-Etv2 通路在造血和心脏命运决定中未被认识到的调控作用。
