Every month, the womb lining rebuilds itself, prepares for a possible pregnancy, and—if no embryo arrives—sheds away. This research aims to understand exactly what goes wrong when that process fails, leading to recurrent miscarriage. The problem is that scientists have never been able to watch, cell by cell, how the endometrium transforms during the crucial days when an embryo would normally implant. Current knowledge is too coarse to pinpoint the faulty molecular switches that cause some women’s wombs to reject embryos. This project will use single-nucleus sequencing to track gene activity and DNA accessibility in every cell type across the menstrual cycle, then link those patterns to whether a pregnancy later succeeds or fails. If successful, this work could identify specific cellular events that predict—or cause—miscarriage. That would allow doctors to diagnose endometrial dysfunction with precision, and the 3D organoid cultures developed here could test new treatments without human trials. In the longer term, understanding these fundamental tissue-remodelling mechanisms might also inform research into wound healing or cancer, where similar cellular programmes go awry.
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The endometrium undergoes iterative cycles of menstrual shedding, regeneration, rapid growth, and differentiation in response to ovarian hormones. During the mid-luteal phase, the endometrium becomes transiently receptive to implantation, heralding the start of a process of intense tissue remodelling, characterized by secretory transformation of glandular epithelium, angiogenesis, differentiation of stromal cells into secretory decidual cells, and activation of specialized immune cells. Several reproductive disorders, including recurrent pregnancy loss, are linked to defects in tissue remodelling at implantation. However, the cellular complexity and dynamic nature of the endometrium have so far precluded precise characterization of the underlying pathological mechanisms and drivers. We will employ high-throughput single-nucleus sequencing to map the dynamic changes in gene expression and chromatin accessibility (cis-regulatory regions) in all endometrial cell types across the luteal phase in defined patient groups. The data will be back-mapped to a future successful pregnancy or miscarriage. This analysis will yield unparalleled insight into the sequence of endometrial events (i.e. changes in cell populations, cellular states, gene expression and transcriptional regulation) leading to a successful or failed pregnancy. Further, 3D organoid cultures, consisting of glands and stroma, will be used to investigate putative drivers of endometrial dysfunction and to evaluate new treatment targets.
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