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 decode the endometrial dynamics of fertile women across the window of implantation and characterize the endometrial deficiency in women with recurrent implantation failure. A computational model capable of both temporal prediction and pattern discovery is used to analyze single-cell transcriptomic data from over 220,000 endometrial cells. The time-series atlas highlights a two-stage stromal decidualization process and a gradual transitional process of the luminal epithelial cells across the window of implantation. In addition, a time-varying gene set regulating epithelium receptivity is identified, based on which the recurrent implantation failure endometria are stratified into two classes of deficiencies. Further investigation uncovers a hyper-inflammatory microenvironment for the dysfunctional endometrial epithelial cells of recurrent implantation failure. The holistic characterization of the physiological and pathophysiological window of implantation and a computational tool trained on this temporal atlas provide a platform for future therapeutic developments. Time-series single-cell transcriptomic characterization of luteal-phase endometrium in fertile women with a variational autoencoder model uncovers the association of decreased epithelial receptivity and hyperinflammatory microenvironment in recurrent implantation failures.