RhoB Promotes Endometrial Stromal Cells Decidualization Via Semaphorin3A/PlexinA4 Signaling in Early Pregnancy

Abstract

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.

Convergent gene expression in epithelial cells illuminates the evolution of uterine receptivity

“…1F, S2; Methods). Examining the function of the top DEGs across species revealed key actors of endometrial receptivity (PGR, ESR1, Asgr2, RPLP2) (Wetendorf et al 2017; Cha, Sun, and Dey 2012; Forde et al 2011; Manohar et al 2014), embryo implantation (KLK11, TPPP3, CDC20B, Gper1) (Wetendorf et al 2017; Cha, Sun, and Dey 2012; Fernando et al 2006; Kolkova et al 2010; Yan and Clarke 2017), decidualization (TPPP3, Gper1, GJA1, PLXNA4, C1rb, Ceacam10) (Kaya et al 2015; Garrido-Gomez et al 2021; Shukla et al 2019; Kolkova et al 2010; Yu et al 2017; Manley et al 2020; Xu et al 2022; Sones et al 2018; Finkenzeller et al 2003), pregnancy outcomes (GSTA3, Kcnj1) (Garrido-Gomez et al 2021; 2017; Lundgren et al 1997) and endometrial dynamic changes during the menstrual cycle (ESR1, PGR, DEUP1, LGALS3) (Gleeson et al 1993; Spassky and Meunier 2017; Okumu et al 2011). Additionally, in each species, around 75% of genes differentially expressed under E2 treatment were also DEGs after E2+P4 treatment (Fig.…”

Semaphorin 3A Increases in the Plasma of Women with Diminished Ovarian Reserve Who Respond Better to Controlled Ovarian Stimulation

“…Interestingly, SEMA3A and SEMA3C expression is markedly increased in women with endometriosis [ 32 ]. SEMA3A was found in greater amounts in the glandular epithelial cells in peritoneal endometriosis and deep infiltrating endometriotic lesions of the uterosacral ligament [ 33 ]. This indicates that SEMA3A, as a nerve-repellent factor, may be responsible for the altered sympathetic innervation of endometriosis.…”

“…In this regard, high SEMA3C levels have been found at the maternal-fetal-placental interface during the first trimester of gestation [39], and SEMA3F, SEMA3B, and NRP2 are overexpressed in the placenta of women with preeclampsia [37,40]. Interestingly, Xu et al (2022) [33] revealed that the expression of SEMA3A was decreased in the decidua of patients who experienced unexplained spontaneous miscarriage. This finding suggests that SEMA3A may have a positive impact on embryo implantation during pregnancy and likely implies that SEMA3A has an impact on aspects of reproduction that involve fetal implantation and continuation of pregnancy.…”