Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion

• microRNAs are secreted by human blastocysts relative to implantation potential during IVF.
• microRNA-661 is secreted by blastocysts that fail to implant and taken up by endometrial epithelial cells via Argonaute 1.
• microRNA-661 reduces adhesion of trophoblast spheroids to endometrial cells.Implantation failure is a large problem affecting the success rate of in vitro fertilisation (IVF). There are no effective treatments for implantation failure. Our study demonstrated that human embryos secrete microRNA and their expression is differentially expressed in embryos that achieve a successful pregnancy compared to embryos that fail. The study identified that microRNA 661 secreted by embryos, was taken up by human endometrial epithelial cells via attachment to a protein and inhibited endometrial cell adhesiveness. This suggests that abnormally produced microRNA may prevent attachment of human embryos to the endometrial lining and prevent implantation and pregnancy.

Successful embryo implantation requires synchronous development and communication between the blastocyst and the endometrium, however the mechanisms of communication in humans are virtually unknown. Recent studies have revealed that microRNAs (miRs) are present in bodily fluids and secreted by cells in culture. We have identified that human blastocysts differentially secrete miRs in a pattern associated with their implantation outcome. miR-661 was the most highly expressed miR in blastocyst culture media (BCM) from blastocysts that failed to implant (non-implanted) compared to blastocysts that implanted (implanted). Our results indicate a possible role for Argonaute 1 in the transport of miR-661 in non-implanted BCM and taken up by primary human endometrial epithelial cells (HEECs). miR-661 uptake by HEEC reduced trophoblast cell line spheroid attachment to HEEC via PVRL1. Our results suggest that human blastocysts alter the endometrial epithelial adhesion, the initiating event of implantation, via the secretion of miR, abnormalities in which result in implantation failure.