Calcineurin A gamma and NFATc3/SRPX2 axis contribute to human embryonic stem cell differentiation
Calcineurin A gamma and NFATc3/SRPX2 axis contribute to human embryonic stem cell differentiation
复制标题
钙调神经磷酸酶 A gamma 和 NFATc3/SRPX2 轴有助于人胚胎干细胞分化
DOI：
10.1002/jcp.30255
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发表时间：
2021-01-03
影响因子：
5.6
通讯作者：
Jin, Ying
中科院分区：
文献类型：
--
作者：
Chen, Hao;Zeng, Yanwu;Jin, Ying
我们对调节人类胚胎干细胞（hESCs）细胞命运的信号通路的了解有限。钙调神经磷酸酶-NFAT信号传导与广泛的生物过程和疾病相关。然而，其在控制hESC命运中的作用仍不清楚。在这里，我们报告说，钙调磷酸酶A γ和NFATc 3/SRPX 2轴控制hESC的谱系和上皮间质转化（EMT）标志物的表达。PPP 3CC（编码钙调磷酸酶A γ或NFATC 3的基因）的敲低在hESC的自我更新状态和分化期间下调某些标志物。此外，NFATc 3与c-JUN相互作用并调节SRPX 2的表达，SRPX 2是编码分泌型糖蛋白的基因，称为uPAR的配体。我们发现SRPX 2是NFATc 3的下游靶点。SRPX 2和uPAR都参与控制谱系和EMT标志物的表达。重要的是，SRPX 2敲低减少了由hESC中NFATc 3和c-JUN的共过表达诱导的多谱系和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NFATc 3/SRPX 2轴在调节hESC命运决定中的先前未知作用。
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.