Functional characterization of mesenchymal-epithelial transition (MET)-derived cells in normal endometrial regeneration

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PROJECT SUMMARY The uterus in women is a unique organ in its ability to undergo repeated physiological damage and repair during the monthly menstrual cycle. The endometrium, in particular, is extensively regenerated following menstrual shedding. Our long-term research goal is to understand the normal mechanisms of endometrial regeneration and repair and how these processes, when mis-regulated, contribute to diseases/dysfunction such as endometrial cancer, endometriosis, thin endometrium, Asherman’s Syndrome and infertility. In this project, experiments are designed to investigate mesenchymal-epithelial transition (MET) as a mechanism of endometrial epithelial regeneration. Research shows that MET is one mechanism by which the endometrial epithelium is regenerated postpartum and in a menses-like model in mice and has been proposed as a mechanism in women. During MET, which is a type of cellular transdifferentiation, a mesenchymal cell is reprogrammed and converted into an epithelial cell. To our knowledge, the endometrium is the only tissue that uses cellular transdifferentiation under normal physiological conditions (e.g. postpartum and menses-like repair) in the adult. Unfortunately, our understanding of this unique repair mechanism is very incomplete. Two specific aims will further investigate MET in epithelial regeneration: (1) Test the function of MET-derived endometrial epithelial cells; and (2) Compare MET by endometrial-derived and bone marrow (BM)-derived mesenchymal cells. A combination of mouse models including lineage tracing, menses-like endometrial breakdown and repair and a novel orthotopic transplantation technique along with scRNA-seq will be employed to address fundamental questions about the function, characteristics, and origin of MET-derived epithelial cells. Particularly, whether they are bona fide endometrial epithelial cells and whether they originate from endometrial stromal cells and/or bone marrow cells, will be investigated. Importantly, orthotopic transplantation will be used to assess MET by human stromal cells as in vivo studies cannot be performed in women. Proper endometrial regeneration, including replacement of lost or damaged epithelial cells, is necessary for preparation of the uterus for subsequent reproductive cycles and pregnancy. No other organ is subject to such extreme tissue regeneration as that seen in the uterus during the menstrual cycle. It is perhaps because of the extent of damage and repair that the uterus undergoes that it is subject to development of diseases. Increased understanding of endometrial repair mechanisms will provide greater insight into how these processes, when gone awry, contribute to endometrial diseases and impact fertility ultimately leading to better therapeutics.