Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Comparative analysis of a newly discovered human endometrial receptivity marker in rhesus macaques and mice (#116)

Bothidah Thach 1 2 3 , Nirukshi Samarajeewa 1 , Ying Li 1 , Sophea Heng 1 , Te-Sha Tsai 1 , Mulyoto Pangestu 4 , Sally Catt 4 , Guiying Nie 1 2
  1. Implantation and Pregnancy Research Laboratory, School of Health and Biomedical Science, RMIT University, Bundoora, VIC, Australia
  2. Hudson Institute of Medical Research, Clayton, VIC, Australia
  3. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
  4. Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia

Background: Podocalyxin (PODXL) is a newly discovered endometrial receptivity marker in women; it is specifically downregulated in the endometrial luminal epithelium at receptivity to permit embryo implantation.

Aim: To determine whether endometrial PODXL expression is conserved between humans, rhesus macaques and mice for embryo implantation.

Methods: The PODXL gene, mRNA and protein sequences across species were compared bioinformatically. Immunohistochemistry and in situ hybridization (mouse tissues) were employed to assess uterine PODXL expression in macaques across the menstrual cycle (n = 3 per phase), and in mice across the estrous cycle (n = 4 per phase) and on pregnant d4.5, when implantation initiates (n = 4). Functional studies then investigated whether endometrial PODXL affects mouse embryo attachment. 

Results: Greater sequence similarities were evident between humans and macaques than with mice. In all species, PODXL was expressed in uterine epithelial and endothelial cells. In macaques, PODXL was downregulated in the luminal epithelium in the mid-secretory phase (****P < 0.0001) when receptivity is developed, consistent with the pattern found in women. At this time, PODXL was also downregulated in shallow (****P < 0.0001) but not in deep (**P < 0.01) glands. Endothelial PODXL was unchanged across the cycle. In mice, uterine PODXL did not vary considerably across the estrous cycle. However, at the time of implantation, PODXL was greatly reduced in the luminal epithelium especially near the site of embryo attachment. Mouse embryos failed to attach or thrive when co-cultured on a monolayer of Ishikawa cells overexpressing PODXL.

Conclusions: Endometrial PODXL is downregulated in the luminal epithelium for embryo implantation in all species examined; PODXL is confirmed to inhibit mouse embryo implantation. The rhesus macaque shares greater conservation with humans than mice in PODXL regulation, and thus represents a better animal model for studying endometrial receptivity for human fertility treatment.