Changes in the cellular composition of the endometrium during the implantation window are associated with recurrent pregnancy loss

Recurrent pregnancy loss (RPL) affects 1-2% of women trying to conceive, yet in many cases the causes remain unclear. Endometrial function is central to the establishment and maintenance of pregnancy, and endometrial dysfunction may underlie RPL. A greater understanding of the endometrial cell populations and their interactions in women with and without RPL may identify markers of endometrial receptivity and the likelihood of pregnancy success. Single cell RNA sequencing was performed on RPL (n = 3) and control (n = 4) endometrial biopsies collected at days 21-24 of the menstrual cycle, the window of implantation. 10,022 cells were clustered and nine major individual cell types were characterised. Further analysis identified six distinct endometrial stromal cell (EnSCs) and three natural killer (NK) cell sub-populations. In RPL, there were changes in the abundance of specific endometrial stromal and NK cell subpopulations with associated differences in cellular communication between the cell types related to the Wnt pathway and angiogenesis. This is consistent with NK cell signalling orchestrating the difference in abundance of stromal cells and regulating processes needed for successful implantation. These changes in RPL endometrium provide further evidence for an endometrial cause of RPL and identify specific mechanisms for future study.