Oral Presentation ESA-SRB-APEG-NZSE 2022

WD-repeat containing protein-61 dysregulation in the endometrial luminal epithelium impairs human endometrial receptivity (#57)

Poppy Downing 1 2 , Wei Zhou 1 2 , Madeleine Howe 1 2 , Leiani Santos 1 2 , Wan Tinn The 1 3 4 5 , Tarana Lucky 3 6 , Evdokia Dimitriadis 1 2
  1. Department of Obstetrics and Gynecology, University of Melbourne, Parkville, Victoria, Australia
  2. Gynaecology Research Centre, Royal Women's Hospital, Parkville, Victoria, Australia
  3. The Royal Women's Hospital, Parkville, Victoria, Australia
  4. Melbourne IVF, Melbourne, Victoria, Australia
  5. Epworth Health Care, Melbourne, Victoria, Australia
  6. School of Medicine, Griffith University, Gold Coast, Queensland, Australia

Endometrial receptivity is a hallmark of successful blastocyst implantation in early pregnancy. A major challenge to successful IVF treatment is recurrent implantation failure (RIF) whereby impaired endometrial receptivity is a major contributor. However, there is no way to identify or treat abnormalities in the endometrium. Recently, we developed endometrial organoids from women with infertility and with normal fertility. We identified that WD-repeat-containing protein-61 (WDR61) was abnormally reduced in apical endometrial epithelial organoid secretions from primary infertile women (N=7). WDR61 is a transcriptional cofactor of the Wnt pathway, which has known roles in endometrial function. We hypothesised that WDR61 plays a role in endometrial receptivity and implantation during the window of implantation (WOI). Our immunohistochemistry data demonstrated WDR61 immunostained in endometrial glands, stroma, and luminal epithelium (N=7). WDR61 was significantly higher during the receptive phase than in the non-receptive, proliferative phase of fertile women (N=8, P<0.05), despite minimal difference in immunostaining levels between fertile and infertile tissues (N=6). To assess function, siRNA knockdown of WDR61 in Ishikawa cells (endometrial epithelial cell-line) was used to assess adhesion and proliferation by xCELLigence real-time monitoring. WDR61 siRNA treatment reduced adhesion and proliferation of Ishikawa cells compared to respective controls (P<0.05). Qualitative-PCR was employed to determine the changes in the expression of genes implicated in blastocyst implantation and development, cell proliferation, and Hox and Wnt pathways. Several pivotal genes such as HOXD10, MMP2, CD44 and CXCR4 were significantly diminished compared to controls (P<0.05). Our data suggests that WDR61 is involved in cyclic changes within the endometrium to prepare for blastocyst implantation during the WOI. When it is dysregulated in vivo, WDR61 may contribute to RIF due to the impaired proliferative and adhesive capacity of the luminal epithelium. These findings could be translated to the clinic to enhance current IVF in women with implantation failure.