Identification of an enzyme promoting post-implantation embryo growth and placental formation — Expectations of mechanistic understanding and development of effective treatments for infertility

Infertility is a problem faced by nearly one in six adults worldwide. Despite recent advances in assisted reproductive technologies, implantation failure, in which pregnancy cannot be achieved even after repeated transfers of good-quality embryos, remains the biggest problem in fertility treatment. Implantation is a process through which the embryo enters the uterus and attaches to the endometrium with multiple steps.

Although implantation must be regulated precisely, the underlying mechanisms remain poorly understood. A research team led by Associate Professor Shizu Aikawa of the Life Science Center for Survival Dynamics, University of Tsukuba, aimed to elucidate the molecular mechanisms involved in embryo implantation, decidualization and placental formation. In a previous study, the team identified that "Hif2α," a protein activated under low-oxygen conditions to regulate gene expression, plays an important role in embryonic invasion during implantation, but the mechanism was not well understood.

In this study, the team analyzed which genes were expressed at which sites of the endometrium where embryonic invasion has occurred. They discovered that Hif2α promotes secretion of an enzyme, "Lysyl oxidase (Lox)," from the endometrium around the embryo attachment site to reorganize the collagen structures in the endometrium during the implantation stage. They demonstrated that Lox-deleted uteri exhibited poor embryo invasion and abnormal placental formation, leading to miscarriages or defective fetal growth.

In humans, cultured cell experiments have shown that trophoblasts highly express Lox under low-oxygen conditions, suggesting that the present findings may have relevance to implantation failures in humans. The findings are expected to contribute to etiological and pathological understanding of infertility and gestational hypertension. (Article: Masanori Nakajo) In normal mice, invasion of green trophoblasts into the endometrium was observed on day 6 of pregnancy (left).

In Lox-deleted mice, abnormal clumps of trophoblasts were observed, with little or no invasion (right). Medicine Biology