2. Academic Validation
  3. EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure

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

  • EBioMedicine. 2019 Dec:50:343-354. doi: 10.1016/j.ebiom.2019.10.018.
Quan Zhou 1,  Guijun Yan 2,  Lijun Ding 2,  Jingyu Liu 2,  Xiaoying Yu 2,  Shuangbo Kong 3,  Mei Zhang 2,  Zhilong Wang 2,  Yang Liu 2,  Yue Jiang 2,  Na Kong 2,  Jianxin Sun 4,  Haixiang Sun 5
Affiliations

Affiliations

  • 1 Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, People's Republic of China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences , Nanjing University , Nanjing 210023, People's Republic of China.
  • 2 Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, People's Republic of China.
  • 3 Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China.
  • 4 Center for Translational Medicine, Thomas Jefferson University, 1025 Walnut Street, Philadelphia 19107, PA, USA. Electronic address: [email protected].
  • 5 Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, People's Republic of China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences , Nanjing University , Nanjing 210023, People's Republic of China. Electronic address: [email protected].
PMID: 31707150 DOI: 10.1016/j.ebiom.2019.10.018
Abstract

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.

Keywords

Decidualization; EHD1; RIF; Wnt4.

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