Mechanisms Governing Uterine Epithelial Plasticity

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Project Summary/Abstract Unlike most other organs and tissues, the endometrium of the adult uterus has a remarkable regenerative ability, undergoing repetitive cycles of proliferation, differentiation, breakdown, and regeneration. The endometrium is a complex tissue comprised of stroma, vasculature and immune cells, as well as two major epithelial cell types — luminal (LE) and glandular (GE) epithelium. Notably, the endometrium repairs after menstruation, injury, and childbirth without scarring and then regenerates with full function to support pregnancy. Aberrations in regeneration negatively impacts pregnancy success and can lead to infertility or diseases, such as endometriosis, endometrial fibroids, Asherman’s syndrome, and endometrial cancer. Thus, the long-term research objective is to define the critical intrinsic and extrinsic mechanisms governing uterine epithelial cell differentiation and regeneration with subsequent impacts to diagnose, treat, and prevent infertility and endometrial disease in women. The regenerative capacity and ability to grow ectopically (endometriosis) suggests that the endometrium has a robust and plastic progenitor population. Indeed, numerous reports have provided evidence that cells with stem cell-like qualities exist in the epithelium of the uterus; however, the identity, behavior, and mechanisms underlying the fate of those cells and their location remains unclear. Ambiguity within the uterine stem cell field may be partly because the strict lineage hierarchies that characterize development and homeostatic tissue turnover are not followed during tissue repair. Recent studies in several organs found that epithelial plasticity and activation of facultative stem cells are common strategies for tissue regeneration in the injury repair process. Therefore, this proposal focuses more on the process used by the uterus to replace lost cells, rather than on the physical entity of a stem cell. The overarching hypothesis is that the uterine epithelium contains cells that are unipotent during normal homeostatic turnover but have the ability to dedifferentiate upon injury to coordinate successful epithelial regeneration. Guided by strong preliminary data and the use of innovative mouse genetic models, organoid culture, and single-cell sequencing technologies, two specific aims will begin testing that hypothesis: (1) epithelial plasticity in the regenerating uterus; and (2) cellular and molecular aspects of LE response to GE ablation. The outcome of the proposed studies will connect epithelial regeneration responses to specific molecular mechanisms of epithelial differentiation and repair. In the long term, an increased understanding of the cellular and molecular mechanisms that govern endometrial epithelial cell differentiation and regeneration is important not only for gaining fundamental knowledge of tissue and stem cell biology but also for the development of therapeutics for the treatment of endometrial diseases.