EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure

Abstract

a b s t r a c tBackground: Recurrent implantation failure (RIF) remains a critical and challenging problem in assisted reproductive technology mainly due to impaired decidualization. The endocytic and transcytotic activity in the endometrium are crucial for decidualization. The most representative endocytic gene is the Cterminal Eps15 homology domain-containing 1 (EHD1), but whether EHD1-mediated endocytic function is responsible for embryo implantation during decidualization remains unclear. Methods: A transcriptomic analysis was performed to evaluate the differentially expressed genes between the fertile control and RIF group. The expression and location of EHD1 in endometrial tissues were further examined by IHC, qRT-PCR and Western blotting. The transduction of an EHD1 recombinant adenovirus into human endometrial stromal cells was performed to investigate relevant decidualization marker genes. Additionally, a microarray analysis following the adenovirus-mediated overexpression of EHD1 was conducted to identify EHD1-related changes in HESCs, and the potential molecular mechanisms were further confirmed through immunofluorescence and coimmunoprecipitation analyses. Findings: An RNA-seq analysis demonstrated that EHD1 expression was significantly higher in the midsecretory endometrium of the RIF group than in that of the fertile control group. The analysis of the menstrual cycle showed that expression of EHD1 increased in the mid-proliferative phase and showed a gradual decrease in the mid-secretory and decidual phases. Furthermore, EHD1 overexpression impaired decidualization by suppressing the expression of prolactin and insulin-like growth factor binding protein-1 and the formation of the cytoskeleton. The mechanistic analysis revealed the EHD1 regulated LRP5/6 protein function through the endocytic pathway, and subsequently suppressed the Wnt4/ β-catenin pathway during decidualization. In addition, a Wnt4 agonist improved an impaired decidualization process. Interpretation: Regulation of the EHD1-Wnt4 pathway might serve as a promising therapeutic strategy for improving endometrial receptivity in RIF women.Recurrent implantation failure (RIF) remains a critical and challenging problem in assisted reproductive technology mainly because of impaired decidualization. Endocytic and transcytotic activity in the endometrium are crucial for impaired decidualization. The most representative endocytic genes is the C-terminal Eps15 homology domain-containing 1 (EHD1). Whether the EHD1https://doi.

Loss of CDYL Results in Suppression of CTNNB1 and Decreased Endometrial Receptivity

“…Among these factors, poor endometrial receptivity is the main cause for RIF (Timeva et al, 2014;Vlachadis et al, 2014;Craciunas et al, 2019). There have been researches using either microarray technology or to identify the transcriptomic signature of endometrial samples from RIF patients (Mahajan, 2015;Zhou et al, 2019). However, the pathogenesis of poor endometrial receptivity in RIF cases has not been fully elucidated yet.…”

Deficiency of Sirtuin 1 Impedes Endometrial Decidualization in Recurrent Implantation Failure Patients

“…The endometrium is receptive to implantation during WOI phase, which requires epithelial cells develop specialized structures known as pinopodes secreting cell adhesion molecules and stromal cells initiates decidual reactions providing a nutritive and immunoprivileged matrix essential for embryo implantation ( Lessey and Young, 2019 ). Recent years, there has been increased lines of evidence demonstrating that RIF patients suffered from impaired endometrial decidualization ( Huang C. et al, 2017 ; Szwarc et al, 2019 ; Zhou et al, 2019 ). Our results also showed that ESCs isolated from RIF patients had a poor response to artificial induced decidualization, manifested by the reduced expression of two decidual markers.…”

“…The RIF group consisted of patients who had undergone three or more previous failed cycles with at least four morphologically high-grade embryos, but failed to conceive in which there was no other explanation after a through infertility work-up ( Ruiz-Alonso et al, 2013 ; Polanski et al, 2014 ; Bashiri et al, 2018 ; Zhou et al, 2019 ). The control (CTRL) group was women who underwent IVF treatment due to tubal factor infertility, and were able to successfully conceive in first transplantation cycle.…”

“…Recurrent implantation failure (RIF) refers to the failure of achieving a pregnancy after at least three in vitro fertilization (IVF) cycles in which one or two high-grade embryos are transferred ( Ruiz-Alonso et al, 2013 ; Polanski et al, 2014 ; Bashiri et al, 2018 ; Zhou et al, 2019 ). Successful implantation requires a receptive endometrium, a functional embryo and a synchronized communication between maternal and embryonic sides ( Neykova et al, 2020 ).…”

CXCL12 enhances pregnancy outcome via improvement of endometrial receptivity in mice

“…Among the factors that attributes to RIF; unreceptive endometrium, poor embryos, and unsynchronized maternal-fetal crosstalk; defects in endometrial receptivity accounts for the half of implantation failures in women suffering from RIF after embryo transfer 11,12 . Although there have been extensive studies to identify the multi-omic signatures of endometrium of women with RIF compared to normal women [13][14][15] , pathophysiological features of the endometrium with poor receptivity have not been fully elucidated yet.…”