Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation

BACKGROUND: Recurrent implantation failure is a critical issue in IVF‐ET treatment. Successful embryo implantation needs appropriate molecular and cellular communications between embryo and uterus. Rodent models have been used intensively to understand these mechanisms. METHODS: The molecular and cellular mechanisms of embryo implantation were described by referring to the previous literature investigated by us and others. The studies using mouse models of embryo implantation were mainly cited. RESULTS: Progesterone (P(4)) produced by ovarian corpus luteum provides the uterus with receptivity to the embryo, and uterine epithelial growth arrest and stromal proliferation, what we call uterine proliferation‐differentiation switching (PDS), take place in the peri‐implantation period before embryo attachment. Uterine PDS is a hallmark of uterine receptivity, and several genes such as HAND2 and BMI1, control uterine PDS by modulating P(4)‐PR signaling. As the next implantation process, embryo attachment onto the luminal epithelium occurs. This process is regulated by FOXA2‐LIF pathway and planar cell polarity signaling. Then, the luminal epithelium at the embryo attachment site detaches from the stroma, which enables trophoblast invasion. This process of embryo invasion is regulated by HIF2α in the stroma. CONCLUSION: These findings indicate that embryo implantation contains multistep processes regulated by specific molecular pathways.