The role of mesenchymal–epithelial transition in endometrial function

Abstract

BACKGROUND: The human uterine endometrium undergoes significant remodeling and regeneration on a rapid and repeated basis, after parturition, menstruation, and in some cases, injury. The ability of the adult endometrium to undergo cyclic regeneration and differentiation/decidualization is essential for successful human reproduction. Multiple key physiologic functions of the endometrium require the cells of this tissue to transition between mesenchymal and epithelial phenotypes, processes known as mesenchymal-epithelial transition (MET) and epithelial-mesenchymal transition (EMT). Although MET/EMT processes have been widely characterized in embryonic development and in the context of malignancy, mounting evidence demonstrates the importance of MET/EMT in allowing the endometrium the phenotypic and functional flexibility necessary for successful decidualization, regeneration/re-epithelialization and embryo implantation. OBJECTIVE AND RATIONALE: The objective of this review is to provide a comprehensive summary of the observations concerning MET and EMT and their regulation in physiologic uterine functions, specifically in the context of endometrial regeneration, decidualization and embryo implantation. SEARCH METHODS: Using variations of the search terms 'mesenchymal-epithelial transition', 'mesenchymal-epithelial transformation', 'epithelial-mesenchymal transition', 'epithelial-mesenchymal transformation', 'uterus', 'endometrial regeneration', 'endometrial decidualization', 'embryo implantation', a search of the published literature between 1970 and 2018 was conducted using the PubMed database. In addition, we searched the reference lists of all publications included in this review for additional relevant original studies. OUTCOMES: Multiple studies demonstrate that endometrial stromal cells contribute to the regeneration of both the stromal and epithelial cell compartments of the uterus, implicating a role for MET in mechanisms responsible for endometrial regeneration and re-epithelialization. During decidualization, endometrial stromal cells undergo morphologic and functional changes consistent with MET in order to accommodate embryo implantation. Under the influence of estradiol, progesterone and multiple other factors, endometrial stromal fibroblasts acquire epithelioid characteristics, such as expanded cytoplasm and rough endoplasmic reticulum required for greater secretory capacity, rounded nuclei, increased expression of junctional proteins which allow for increased cell-cell communication, and a reorganized actin cytoskeleton. During embryo implantation, in response to both maternal and embryonic-derived signals, the maternal luminal epithelium as well as the decidualized stromal cells acquire the mesenchymal characteristics of increased migration/motility, thus undergoing EMT in order to accommodate the invading trophoblast. WIDER IMPLICATIONS: Overall, the findings support important roles for MET/EMT in multiple endometrial functions required for successful reproduction. The endometrium may be considered a unique wound healing model, given its ability to repeatedly undergo repair without scarring or loss of function. Future studies to elucidate how MET/EMT mechanisms may contribute to scar-free endometrial repair will have considerable potential to advance studies of wound healing mechanisms in other tissues.