Cargando…
EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure
BACKGROUND: 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 i...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921214/ https://www.ncbi.nlm.nih.gov/pubmed/31707150 http://dx.doi.org/10.1016/j.ebiom.2019.10.018 |
_version_ | 1783481111646568448 |
---|---|
author | Zhou, Quan Yan, Guijun Ding, Lijun Liu, Jingyu Yu, Xiaoying Kong, Shuangbo Zhang, Mei Wang, Zhilong Liu, Yang Jiang, Yue Kong, Na Sun, Jianxin Sun, Haixiang |
author_facet | Zhou, Quan Yan, Guijun Ding, Lijun Liu, Jingyu Yu, Xiaoying Kong, Shuangbo Zhang, Mei Wang, Zhilong Liu, Yang Jiang, Yue Kong, Na Sun, Jianxin Sun, Haixiang |
author_sort | Zhou, Quan |
collection | PubMed |
description | BACKGROUND: 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 C-terminal 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 mid-secretory 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. |
format | Online Article Text |
id | pubmed-6921214 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-69212142019-12-27 EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure Zhou, Quan Yan, Guijun Ding, Lijun Liu, Jingyu Yu, Xiaoying Kong, Shuangbo Zhang, Mei Wang, Zhilong Liu, Yang Jiang, Yue Kong, Na Sun, Jianxin Sun, Haixiang EBioMedicine Research paper BACKGROUND: 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 C-terminal 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 mid-secretory 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. Elsevier 2019-11-06 /pmc/articles/PMC6921214/ /pubmed/31707150 http://dx.doi.org/10.1016/j.ebiom.2019.10.018 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Zhou, Quan Yan, Guijun Ding, Lijun Liu, Jingyu Yu, Xiaoying Kong, Shuangbo Zhang, Mei Wang, Zhilong Liu, Yang Jiang, Yue Kong, Na Sun, Jianxin Sun, Haixiang EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure |
title | EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure |
title_full | EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure |
title_fullStr | EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure |
title_full_unstemmed | EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure |
title_short | EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure |
title_sort | ehd1 impairs decidualization by regulating the wnt4/β-catenin signaling pathway in recurrent implantation failure |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921214/ https://www.ncbi.nlm.nih.gov/pubmed/31707150 http://dx.doi.org/10.1016/j.ebiom.2019.10.018 |
work_keys_str_mv | AT zhouquan ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT yanguijun ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT dinglijun ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT liujingyu ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT yuxiaoying ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT kongshuangbo ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT zhangmei ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT wangzhilong ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT liuyang ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT jiangyue ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT kongna ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT sunjianxin ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure AT sunhaixiang ehd1impairsdecidualizationbyregulatingthewnt4bcateninsignalingpathwayinrecurrentimplantationfailure |