Progesterone suppresses podocalyxin partly by up-regulating miR-145 and miR-199 in human endometrial epithelial cells to enhance receptivity in in vitro models.

Establishment of endometrial surface receptivity is crucial for the initiation of embryo implantation yet the molecular mechanisms are not well understood, especially in humans. We have recently discovered that podocalyxin (PODXL) is a critical negative regulator of human endometrial surface receptivity. PODXL is highly expressed in all epithelial and endothelial cells in the non-receptive endometrium, but down-regulated specifically in the luminal epithelium at receptivity. We have further shown that PODXL inhibits embryo implantation, and that PODXL down-regulation is essential for endometrial surface receptivity. Our previous study also indicated that progesterone down-regulates PODXL; however, the exact molecular regulations are unknown. Here, we investigated whether progesterone suppresses PODXL via microRNAs (miRNAs). We first bioinformatically predicted 13 miRNAs that may potentially target human PODXL, then experimentally determined whether any of these 13 miRNAs are altered in primary human endometrial epithelial cells (HEECs) by progesterone, and whether the identified miRNAs can affect PODXL expression in Ishikawa cells without progesterone and alter receptivity to embryo implantation. Progesterone significantly up-regulated miR-145 and miR-199 while suppressing PODXL in HEECs. When these two miRNAs were transfected into Ishikawa cells, both significantly down-regulated PODXL mRNA and protein in the absence of progesterone. Moreover, both miR-145 and miR-199 significantly enhanced receptivity of the Ishikawa monolayer to embryo implantation in in vitro models. This study thus provides in vitro evidence that PODXL is down-regulated by progesterone partly via miR-145 and miR-199 during the development of human endometrial epithelial receptivity. These results also reveal the likely importance of hormonal regulation of miRNAs for embryo implantation.

MicroRNAs in the Regulation of Endometrial Receptivity for Embryo Implantation.

Development of endometrial receptivity is crucial for successful embryo implantation and pregnancy initiation. Understanding the molecular regulation underpinning endometrial transformation to a receptive state is key to improving implantation rates in fertility treatments such as IVF. With microRNAs (miRNAs) increasingly recognized as important gene regulators, recent studies have investigated the role of miRNAs in the endometrium. Studies on miRNAs in endometrial disorders such as endometriosis and endometrial cancer have been reviewed previously. In this minireview, we aim to provide an up-to-date knowledge of miRNAs in the regulation of endometrial receptivity. Since endometrial remodelling differs considerably between species, we firstly summarised the key events of the endometrial cycle in humans and mice and then reviewed the miRNAs identified so far in these two species with likely functional significance in receptivity establishment. To date, 29 miRNAs have been reported in humans and 15 miRNAs in mice within various compartments of the endometrium that may potentially modulate receptivity; miRNAs regulating the Wnt signalling and those from the let-7, miR-23, miR-30, miR-200 and miR-183 families are found in both species. Future studies are warranted to investigate miRNAs as biomarkers and/or therapeutic targets to detect/improve endometrial receptivity in human fertility treatment.