NR4A1 Affects Endometrial Receptivity by Participating in Mesenchymal–Epithelial Transition of Endometrial Stromal Cells

In preparation for embryo implantation, endometrial stromal cells (ESC) undergo differentiation, termed decidualisation. Enhancing endometrial decidualisation may overcome reduced endometrial receptivity, a major limiting factor in natural and assisted reproduction. To determine whether seminal plasma (SP) influences decidualisation, primary human ESC were treated with progesterone (P4, 50 ng mL–1) in the presence or absence of dialysed SP (0.5%) for 24 h or for up to 27 days to investigate immediate early effects or the effects of prolonged exposure, respectively. Combined SP and P4 treatment induced ESC morphological differentiation. Relative to control, P4 alone, and SP alone combined treatment with SP and P4 for 27 days significantly upregulated mRNA levels of the decidua-specific markers prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP1). Consistently, PRL protein secretion was significantly increased over the course of 27 days combined SP and P4 treatment relative to control, P4 alone and SP alone. Likewise, IGFBP1 secretion was significantly greater relative to control and P4 alone over the course of 27 days. Thus, SP enhances and accelerates P4-mediated decidualisation of human ESC and may enhance endometrial receptivity.

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Blockade of transforming growth factor β (TGF-β) restores markers of endometrial receptivity in fibroid-exposed endometrial stromal cells (esc)

Fertility and Sterility ◽

10.1016/j.fertnstert.2012.07.216 ◽

2012 ◽

Vol 98 (3) ◽

pp. S61 ◽

Cited By ~ 1

Author(s):

L.F. Doherty ◽

H.S. Taylor

Keyword(s):

Growth Factor ◽

Stromal Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Endometrial Receptivity ◽

Endometrial Stromal Cells

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Decreased Indian hedgehog signaling activates autophagy in endometriosis and adenomyosis

Reproduction ◽

10.1530/rep-20-0172 ◽

2020 ◽

Author(s):

Yingying Zhou ◽

Yangying Peng ◽

Qingqing Xia ◽

Dewen Yan ◽

Huiping Zhang ◽

...

Keyword(s):

Stromal Cells ◽

Hedgehog Signaling ◽

Endometrial Receptivity ◽

Indian Hedgehog ◽

Marker Protein ◽

Endometrial Stromal Cells ◽

Endometrial Cells ◽

Molecule Inhibitor ◽

Gynecological Diseases ◽

Autophagic Activity

Indian hedgehog (Ihh) signaling regulates endometrial receptivity and is an indispensable mediator of embryonic implantation. Hedgehog signaling is known to regulate autophagy, and aberrant regulation of autophagy is critically implicated in the pathogenesis of endometriosis and adenomyosis. However, potential dysregulation of Ihh signaling and its role in autophagy modulation in these diseases remain obscure. In this study, we found that components of Ihh signaling were significantly decreased, whereas the autophagy marker protein, LC3BII, was significantly increased in endometrial tissues of women with endometriosis or adenomyosis. Inhibition of Ihh signaling with the small molecule inhibitor, GANT61, or Gli1 silencing in primary endometrial stromal cells increased autophagic activity, as measured by the LC3 turnover assay and tandem mCherry-eGFP-LC3B fluorescence microscopy. Furthermore, we observed that GANT61 treatment significantly attenuated hydrogen peroxide-induced cell death, whereas disruption of autophagy with chloroquine diminished this effect. Collectively, these findings reveal that Ihh signaling is suppressed in endometrial tissues of patients with endometriosis or adenomyosis. This abnormal decrease may contribute to endometrial autophagy activation, which may promote aberrant survival of endometrial cells in ectopic sites in these two gynecological diseases.

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Emodin Inhibits Migration and Invasion of Human Endometrial Stromal Cells by Facilitating the Mesenchymal–Epithelial Transition Through Targeting ILK

Reproductive Sciences ◽

10.1177/1933719116645192 ◽

2016 ◽

Vol 23 (11) ◽

pp. 1526-1535 ◽

Cited By ~ 10

Author(s):

Qiaomei Zheng ◽

Ying Xu ◽

Jingjing Lu ◽

Jing Zhao ◽

Xuan Wei ◽

...

Keyword(s):

Stromal Cells ◽

Migration And Invasion ◽

Endometrial Stromal Cells ◽

Mesenchymal Epithelial Transition

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Decreased CD44v3 Expression Impairs Endometrial Stromal Cell Decidualization in Women With Recurrent Implantation Failure

10.21203/rs.3.rs-1043935/v1 ◽

2021 ◽

Author(s):

Xiaowei Zhou ◽

Yi Cao ◽

mingjuan Zhou ◽

Mi Han ◽

mengyu Liu ◽

...

Keyword(s):

Stromal Cells ◽

Culture System ◽

Embryo Implantation ◽

Group Identification ◽

Endometrial Receptivity ◽

Implantation Failure ◽

Recurrent Implantation Failure ◽

Secretory Phase ◽

Endometrial Stromal Cells ◽

Cd44 Isoforms

Abstract BackgroundThe precise pathogenesis of poor endometrial receptivity in recurrent implantation failure (RIF) still remains unclear. This study aims to explore the effects of different CD44 isoforms in the mid-secretory phase endometrium on endometrial receptivity in women with RIF.MethodsMid-secretory phase endometrial tissue samples were obtained from two groups of women who had undergone IVF: a) 24 patients with RIF, b) 18 patients with infertility due to tubal obstruction, who had achieved a successful clinical pregnancy after the first embryo transfer in IVF (control group). Identification of differentially expressed CD44 isoforms in endometrial tissues was assessed with immunohistochemistry, qPCR and western blotting. Effects of CD44v3 overexpression and knockdown on proliferation and decidualization of Immortalized human endometrial stromal cells (T-HESCs) and primary HESCs were investigated by qPCR and Western blot. A heterologous co-culture system of embryo implantation was constructed to mimics the process of trophoblast invasion during implantation.ResultsCD44v3 was significantly higher expressed in mid-secretory phase of endometrial stromal cells than proliferation phase, but was notably lower in RIF patients. The expression of decidualization markers, prolactin (PRL) and insulin like growth factor binding protein-1 (IGFBP1), was notably decreased following CD44v3 knockdown, whereas the expression levels of both PRL and IGFBP1 increased after CD44v3 overexpression in HESCs. Furthermore, the CD44v3-knockdown HESCs displayed a significantly deficiency in supporting trophoblast outgrowth through a co-culture system of embryo implantation; however, CD44v3 overexpression in HESCs promoted trophoblast outgrowth.ConclusionThe reduced expression of CD44v3 suppresses HESCs proliferation and decidualization, which might play a pivotal role in poor endometrial receptivity in women with RIF.

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miR-200 Regulates Endometrial Development During Early Pregnancy

Molecular Endocrinology ◽

10.1210/me.2016-1050 ◽

2016 ◽

Vol 30 (9) ◽

pp. 977-987 ◽

Cited By ~ 19

Author(s):

Patricia T. Jimenez ◽

Monica A. Mainigi ◽

R. Ann Word ◽

W. Lee Kraus ◽

Carole R. Mendelson

Keyword(s):

Zinc Finger ◽

Early Pregnancy ◽

Stromal Cells ◽

Molecular Mechanisms ◽

Morphological Changes ◽

Embryo Implantation ◽

Endometrial Stromal Cells ◽

E Box ◽

Mesenchymal Epithelial Transition

Abstract For successful embryo implantation, endometrial stromal cells must undergo functional and morphological changes, referred to as decidualization. However, the molecular mechanisms that regulate implantation and decidualization are not well defined. Here we demonstrate that the estradiol- and progesterone-regulated microRNA (miR)-200 family was markedly down-regulated in mouse endometrial stromal cells prior to implantation, whereas zinc finger E-box binding homeobox-1 and -2 and other known and predicted targets were up-regulated. Conversely, miR-200 was up-regulated during in vitro decidualization of human endometrial stromal cells. Knockdown of miR-200 negatively affected decidualization and prevented the mesenchymal-epithelial transition-like changes that accompanied decidual differentiation. Notably, superovulation of mice and humans altered miR-200 expression. Our findings suggest that hormonal alterations that accompany superovulation may negatively impact endometrial development and decidualization by causing aberrant miR-200 expression.

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