Glandular Epithelium and Unexplained Recurrent Implantation Failure

Recurrent Implantation Failure (RIF), which refers to the failure to achieve clinical pregnancy following embryo transfer repetitively, continues to be a major obstacle in assisted reproductive technology. RIF could be caused by many disease and most of which is related to abnormal endometrium. However, unexplained RIF is a special situation which puzzles doctors and patients. We use single-cell RNA sequencing to investigate the endometrial mechanism in unexplained RIF because the complicated environment of endometrium. Our results showed endometrium of RIF had higher levels of proliferation and activation of cytotoxic CD8+ T cells, which reject embryo implantation. Furthermore, glandular epithelium exhibits the highest metabolic activity, and it showed abnormal glycolysis and lower lactic acid production in the RIF, which was characterized by lower expression of genes related to glucose intake (SLC12A1), glucose metabolism (ALDOA), lactic acid production (LDHA) and output (SLC16A4) compared with the counterpart in the normal. The suppressive effect of lactic acid on CD8+ T cells was verified in vivo and vitro. We propose that RIF endometrium has not established the immune tolerance to embryo, which was attributed the abnormal glycolysis and lower lactic acid production in glandular epithelium.