Embryonic HBEGF regulates FoxO1 through PI3K signaling as embryo breaches maternal epithelial barrier

Purpose: The initial barrier encountered by the embryo during the pivotal phase of implantation and subsequent pregnancy maintenance is the maternal endometrial epithelial barrier. This study aims to elucidate the interaction between the FoxO1 molecule, which is present in the endometrial lumen epithelium during mouse embryo implantation, and the embryonic HBEGF and PI3K signaling pathways, along with their potential roles in modulating the epithelial barrier. Methods: A normal pregnancy group and a pseudopregnancy model established through uterine bead transfer (using BSA- or HBEGF-coated beads with or without the PI3K inhibitor Wortmannin) were analyzed by comprehensive immunofluorescence, providing insights into the distinct expression patterns and probable functions of HBEGF and FoxO1 within the endometrial milieu. Results: Pharmacological inhibition of PI3K by Wortmannin suppresses HBEGF expression and disrupts FoxO1 signaling in the luminal epithelium, leading to nuclear accumulation of FoxO1 in the crypt epithelium and ultimately preventing luminal closure required for implantation. Conclusions: This research underscores the critical role of PI3K, HBEGF, and FoxO1 signaling in facilitating the embryo’s ability to breach the epithelial barrier during implantation.