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

Understanding human endometrial dynamics remains a challenge, limiting early diagnosis and treatment of reproductive disorders. Here, we decoded the normal endometrial dynamics across the window of implantation (WOI) and its deficiency in endometrium from women with recurrent implantation failure (RIF) by analyzing data from over 220,000 cells, together with developing a computational model StemVAE that is capable of both temporal prediction and pattern discovery. Our time-series atlas highlighted a two-stage stromal decidualization process whereas a gradual epithelial transitional process across the WOI allowing the identification of a time-varying gene set regulating epithelial receptivity. The epithelial receptivity genes were able to stratify the RIF endometrium into two classes of receptivity-deficiency involving early and late implantation. Further investigation uncovered epithelial cell dysfunction under hyperinflammatory microenvironment in RIF endometrium. The holistic characterization of physiological and pathophysiological WOI, and a computational tool trained on this temporal atlas provide a platform for future therapeutic developments.