RhoB Promotes Endometrial Stromal Cells Decidualization Via Semaphorin3A/plexinA4 Signaling in Early Pregnancy
RhoB Promotes Endometrial Stromal Cells Decidualization Via Semaphorin3A/plexinA4 Signaling in Early Pregnancy
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RhoB 在妊娠早期通过 Semaphorin3A/plexinA4 信号传导促进子宫内膜基质细胞蜕膜化
DOI：
10.1210/endocr/bqac134
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发表时间：
2022
期刊：
影响因子：
4.8
通讯作者：
Meirong Du
中科院分区：
文献类型：
--
作者：
Ling Xu;Yan Hong Li;Wei Jie Zhao;Yi Fei Sang;Jia Jia Chen;Da-Jin Li;Meirong Du
子宫内膜脱体化是指卵巢排卵后，在卵巢分泌的雌激素和黄体酮的作用下，子宫内膜为接受胚胎而发生的一系列形态变化和功能重塑。在蜕质化过程中，子宫内膜基质细胞（ESCs）增殖并分化为蜕质基质细胞（dsc），经历细胞骨架重排介导的形态学改变并表达蜕质化标志物，如胰岛素样生长因子结合蛋白-1 （IGFBP1）和泌乳素（PRL）。Ras同源蛋白（Rho）是一个小G蛋白家族，被认为是细胞形态的调节剂，并参与多种其他细胞过程。在本研究中，我们发现ras同源家族成员B （RHOB）在人原代ESCs体外脱体细胞化后是Rho蛋白家族中表达上调最显著的基因。RhoB的表达主要受环磷酸腺苷(cAMP)/蛋白激酶A (PKA)/cAMP反应元件结合蛋白（CREB）信号通路的诱导，部分受孕激素信号通路的诱导。在ESCs中，RhoB的下调可显著抑制肌动蛋白细胞骨架重排、细胞形态转化和IGFBP1的上调，表明RhoB在去个性化中起着不可或缺的作用。从机制上讲，RhoB的下游靶点是信号蛋白3a (Sema3A)，它通过与受体plexinA4相互作用介导RhoB的信号传导。更重要的是，在原因不明的自然流产患者的蜕膜中检测到RhoB、Sema3A和plexinA4的表达降低。综上所述，我们的研究结果表明RhoB/Sema3A/plexinA4信号通路在子宫内膜脱个体化中发挥积极作用，并与原因不明的自发性流产有关，值得进一步探索，从而为脱个体化不良相关妊娠疾病的治疗策略提供新的见解。
Endometrial decidualization refers to a series of morphological changes and functional remodeling of the uterine endometrium to accept the embryo under the effect of estrogen and progesterone secreted by ovaries after ovulation. During decidualization, endometrial stromal cells (ESCs) proliferate and differentiate into decidual stromal cells (DSCs), undergoing cytoskeletal rearrangement-mediated morphological changes and expressing decidualization markers, such as insulin-like growth factor-binding protein-1 (IGFBP1) and prolactin (PRL). Ras homology (Rho) proteins, a family of small G proteins, are well-known as regulators of cellular morphology and involved in multiple other cellular processes. In this study, we found ras homolog family member B (RHOB) was the most significantly upregulated gene in Rho protein family after the in vitro decidualization of human primary ESCs. RhoB expression was induced mainly by cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling and partly by progesterone signaling. Knockdown of RhoB in ESCs greatly inhibited actin cytoskeletal rearrangement, cell morphological transformation and upregulation of IGFBP1, suggesting an indispensable role of RhoB in decidualization. Mechanistically, the downstream target of RhoB was Semaphorin3A (Sema3A) which mediated its signaling via interacting with the receptor, plexinA4. More importantly, decreased expression of RhoB, Sema3A and plexinA4 were detected in deciduas from patients with unexplained spontaneous miscarriage. Collectively, our results indicate that RhoB/Sema3A/plexinA4 signaling plays a positive role in endometrial decidualization and relates to unexplained spontaneous miscarriage, which is worthy of further exploration so as to provide new insights into therapeutic strategies for pregnancy diseases associated with poor decidualization.