Our understanding of signaling pathways regulating the cell fate of human embryonic stem cells (hESCs) is limited. Calcineurin‐NFAT signaling is associated with a wide range of biological processes and diseases. However, its role in controlling hESC fate remains unclear. Here, we report that calcineurin A gamma and the NFATc3/SRPX2 axis control the expression of lineage and epithelial–mesenchymal transition (EMT) markers in hESCs. Knockdown of PPP3CC, the gene encoding calcineurin A gamma, or NFATC3, downregulates certain markers both at the self‐renewal state and during differentiation of hESCs. Furthermore, NFATc3 interacts with c‐JUN and regulates the expression of SRPX2, the gene encoding a secreted glycoprotein known as a ligand of uPAR. We show that SRPX2 is a downstream target of NFATc3. Both SRPX2 and uPAR participate in controlling expression of lineage and EMT markers. Importantly, SRPX2 knockdown diminishes the upregulation of multiple lineage and EMT markers induced by co‐overexpression of NFATc3 and c‐JUN in hESCs. Together, this study uncovers a previously unknown role of calcineurin A gamma and the NFATc3/SRPX2 axis in modulating the fate determination of hESCs.

中文翻译：

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钙调神经磷酸酶 A γ 和 NFATc3/SRPX2 轴有助于人胚胎干细胞分化

我们对调节人类胚胎干细胞 (hESCs) 细胞命运的信号通路的理解是有限的。钙调神经磷酸酶-NFAT 信号与广泛的生物过程和疾病有关。然而，其在控制 hESC 命运中的作用仍不清楚。在这里，我们报告钙调神经磷酸酶 A γ 和 NFATc3/SRPX2 轴控制 hESC 中谱系和上皮 - 间充质转化 (EMT) 标记的表达。PPP3CC（编码钙调神经磷酸酶 A γ 或NFATC3的基因）的敲低会在 hESC 的自我更新状态和分化过程中下调某些标志物。此外，NFATc3 与 c-JUN 相互作用并调节SRPX2的表达，该基因编码称为 uPAR 配体的分泌糖蛋白。我们证明SRPX2是NFATc3的下游目标。SRPX2 和 uPAR 都参与控制谱系和 EMT 标记的表达。重要的是，SRPX2敲低减弱了 hESC 中 NFATc3 和 c-JUN 共过表达诱导的多个谱系和 EMT 标志物的上调。总之，这项研究揭示了钙调神经磷酸酶 A γ 和 NFATc3/SRPX2 轴在调节 hESC 的命运决定中的先前未知的作用。