Mechanisms of Endometrial Regeneration

Thesis (Ph.D.), Animal Sciences, Washington State UniversityThe uterus is one of the most plastic adult organs with tremendous regenerative capacity. The endometrium (innermost lining of the uterus) undergoes regular cycles of remodeling by transitioning through stages of growth, differentiation, degeneration and regeneration. Remodeling and regeneration of the endometrium occur during pregnancy and following parturition in all mammalian species. Mechanisms coordinating regeneration of the endometrium during the menstrual/estrous cycle and following parturition are poorly understood. Hypothesized mechanisms include proliferation/migration of residual epithelium, cellular transdifferentiation, engraftment of bone marrow-derived cells and contribution of endometrial stem/progenitor cells. Herein, experiments were designed to determine the contributions of cellular transdifferentiation (i.e., mesenchymal-to-epithelial transition; MET), residual glandular epithelium (GE) and stem/progenitor cells to regeneration using mouse models. In the first study, in vivo fate-mapping and characterization of epithelial-mesenchymal transitional cells revealed a role for MET in endometrial regeneration. In the second study, temporal regenerative changes were assessed in regards to glandular GE and efforts were made to identify signaling factors that direct endometrial regeneration. It was determined that GE likely contributes to re-epithelialization of the lumen and the regenerative process is not dependent on estrogen receptor alpha, but rather, relies on paracrine signaling. The third study demonstrated the use of histone H2B-GFP label-retaining transgenic mice as a method to enrich for endometrial stem/progenitor cells. Most importantly, in the fourth study a novel model for transplantation into regenerating uteri was developed to determine the presence and function of candidate endometrial stem/progenitor cells. This model will serve as an invaluable tool for identifying endometrial stem/progenitor cells and evaluating their functional contributions to regeneration, homeostasis and pregnancy. It is reasoned that a more complete understanding of the complex mechanisms of endometrial regeneration will provide insight into how these processes may contribute to uterine disease and infertility when not properly regulated.Animal Sciences, Washington State Universit