Inhibition of YAP/TAZ-TEAD activity induces cytotrophoblast differentiation into syncytiotrophoblast in human trophoblast
Inhibition of YAP/TAZ-TEAD activity induces cytotrophoblast differentiation into syncytiotrophoblast in human trophoblast
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DOI：
10.1093/molehr/gaac032
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发表时间：
2022-09-29
影响因子：
4
通讯作者：
Yoshida，Yoshio
中科院分区：
文献类型：
--
作者：
Mizutani，Tetsuya;Orisaka，Makoto;Yoshida，Yoshio
在胎盘形成期间，胎盘细胞滋养层 (CT) 细胞分化为合体滋养层 (ST) 细胞和绒毛外滋养层 (EVT) 细胞。在胎盘中，各种基因的表达由 Hippo 通路通过转录复合体、Yes 相关蛋白 (YAP)/具有 PDZ 结合基序 (TAZ)-TEA 结构域转录因子 (TEAD) (YAP/TAZ-TEAD) 活性的转录共激活子来调节。 YAP/TAZ-TEAD 活性受多种因素和信号传导控制，例如 cAMP 信号传导。 cAMP 信号传导被认为参与滋养层功能的调节，但尚未完全了解。在这里，我们证明了人绒毛膜癌细胞系 BeWo 细胞中 YAP/TAZ-TEAD 的表达及其活性通过 cAMP 刺激而改变。在没有 cAMP 刺激的情况下，YAP/TAZ-TEAD 活性的抑制诱导 ST 特异性基因的表达，而组成型活性 YAP（即 YAP-5SA）的转导，导致以 TEAD 依赖性方式抑制 8Br-cAMP 诱导的 ST 特异性基因的表达。我们还研究了 YAP/TAZ-TEAD 在维持 CT 细胞及其使用人滋养层干 (TS) 细胞分化为 ST 和 EVT 细胞方面的作用。 YAP/TAZ-TEAD 活性参与维持 TS 细胞的干性。 YAP/TAZ-TEAD 活性的诱导或抑制导致 ST 特异性基因表达的显着变化。使用自发分化为 ST 样细胞的原代 CT 细胞，研究了 YAP-5SA 转导的效果，发现 ST 特异性基因的表达受到抑制。这些结果表明，无论有或没有cAMP刺激，YAP/TAZ-TEAD活性的抑制对于CT细胞向ST细胞的分化都是必需的。
During placentation, placental cytotrophoblast (CT) cells differentiate into syncytiotrophoblast (ST) cells and extravillous trophoblast (EVT) cells. In the placenta, the expression of various genes is regulated by the Hippo pathway through a transcription complex, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ)-TEA domain transcription factor (TEAD) (YAP/TAZ-TEAD) activity. YAP/TAZ-TEAD activity is controlled by multiple factors and signaling, such as cAMP signaling. cAMP signaling is believed to be involved in the regulation of trophoblast function but is not yet fully understood. Here we showed that YAP/TAZ-TEAD expressions and their activities were altered by cAMP stimulation in BeWo cells, a human choriocarcinoma cell line. The repression of YAP/TAZ-TEAD activity induced the expression of ST-specific genes without cAMP stimulation, and transduction of constitutively active YAP, i.e. YAP-5SA, resulted in the repression of 8Br-cAMP-induced expressions of ST-specific genes in a TEAD-dependent manner. We also investigated the role of YAP/TAZ-TEAD in maintaining CT cells and their differentiation into ST and EVT cells using human trophoblast stem (TS) cells. YAP/TAZ-TEAD activity was involved in maintaining the stemness of TS cells. Induction or repression of YAP/TAZ-TEAD activity resulted in marked changes in the expression of ST-specific genes. Using primary CT cells, which spontaneously differentiate into ST-like cells, the effects of YAP-5SA transduction were investigated, and the expression of ST-specific genes was found to be repressed. These results indicate that the inhibition of YAP/TAZ-TEAD activity, with or without cAMP stimulation, is essential for the differentiation of CT cells into ST cells.