Time-series single-cell transcriptomic profiling of luteal-phase endometrium uncovers dynamic characteristics and its dysregulation in recurrent implantation failures

Understanding human endometrial dynamics in the establishment of endometrial receptivity remains a challenge, which limits early diagnosis and treatment of endometrial-factor infertility. Here, we decoded the endometrial dynamics of fertile women across the window of implantation (WOI) and characterized the endometrial deficiency in women with recurrent implantation failure (RIF). A computational model StemVAE capable of both temporal prediction and pattern discovery was used to analyze single-cell transcriptomic data from over 220,000 endometrial cells. The time-series atlas highlighted a two-stage stromal decidualization process and a gradual transitional process of the epithelial cells across the WOI. In addition, a time-varying gene set regulating receptivity of the epithelium was identified. Based on the epithelial receptivity genes, the RIF endometria were stratified into two classes with deficiencies involving early and late implantation processes. Further investigation uncovered that the dysfunctioned endometrial epithelial cells were in a hyper-inflammatory microenvironment in RIF. The holistic characterization of the physiological and pathophysiological WOI and a computational tool trained on this temporal atlas provide a platform for future therapeutic developments.