During embryo implantation blastocysts appose and firmly adhere to a receptive endometrium initiating implantation: adhesion leads to implantation failure/infertility. Whilst IVF is an important intervention for infertility, implantation failure is still a critical limiting factor for IVF success: alarmingly ~ 70% of IVF embryos fail to implant. There is very little known of human blastocyst-endometrial interactions largely due to ethical considerations in obtaining human material. Identifying the critical regulators at the time of implantation may identify targets to facilitate implantation during IVF.
To address this gap in knowledge we developed a unique model where we collected blastocyst conditioned media from clinical left overs from blastocysts that were transferred during IVF and either successfully implanted or did not implant. We used this media to treat primary human endometrial epithelial cells in vitro and demonstrated, for the first time, that IVF blastocysts release factors that alter endometrial adhesion and gene expression relative to implantation and pregnancy outcome during IVF (Cuman C et al, 2013). Blastocysts that implanted after transfer in vivo facilitated adhesion while blastocysts that did not implant had no effect.
Our pilot studies have identified that small non-coding RNAs, microRNAs (miRs), were present in blastocyst conditioned media (BCM), and using miR array analysis we identified that the levels of certain miRs were differentially altered in blastocyst conditioned media from blastocysts that implanted compared to those that did not implant. Extracellular miRs are known to be taken up by cells and alter cell function. We propose that blastocysts release miRs in vivo which regulate blastocyst-endometrial interactions during implantation. Blastocysts that are destined for implantation failure will release miR abnormally and will alter implantation and result in infertility. In the present proposal we aim to confirm our findings and determine the effect of the identified differentially altered miRs on trophectoderm-endometrial adhesion in vitro, the initiating event of implantation. This will provide functional in vitro evidence for the first time for whether targeting these interactions during embryo transfer may facilitate implantation.
Reference: Cuman C, Menkhorst EM, Rombauts LJ, Holden S, Webster D, Bilandzic M, et al. Preimplantation human blastocysts release factors that differentially alter human endometrial epithelial cell adhesion and gene expression relative to IVF success. Hum Reprod. 2013 May;28(5):1161-71.
Reference: Cuman C, Van Sinderen M, Gantier MP, Rainczuk K, Sorby K, Rombauts L, et al. Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion. EBioMedicine. 2015 Oct;2(10):1528-35.