IN VITRO MODELS OF ENDOMETRIOSIS

There is mounting evidence that retrograde menstruation and implantation of endometrial fragments are the primary factors responsible for development of the majority of endometriotic lesions. Many crucial questions concerning the initial interaction of endometrial cells with the peritoneum remain unsettled. Until recently, the manner of endometrial cell attachment to the peritoneum was controversial. Specifically, it was debated whether endometrial cells attach to intact, viable mesothelium (i.e. the epithelium lining of the peritoneum). Tissues serving as a surrogate for the peritoneum, such as the amnion and the chicken chorioallantoic membrane, have been used to evaluate the genesis of the early endometriotic lesion. These studies have led some investigators to postulate that PMCs are a barrier to attachment of ectopic cells to the peritoneum. These investigators hypothesize that trauma to the mesothelial lining is a prerequisite for endometrial adhesion. Studies using whole explants of human peritoneum, as well as peritoneal mesothelial cell (PMC) monolayer cultures, demonstrate that whole fragments of proliferative, secretory, and menstrual phase endometrium, as well as cultured endometrial stromal and epithelial cells (ESCs and EECs, respectively) adhere to intact PMCs within one hour. There is a significant variability in the rate of endometrial binding to PMCs. This variability is mostly dependent on the source of endometrium rather than the source of PMCs. Following attachment to the peritoneum, the early endometriotic lesion is rapidly invasive. Endometrial invasion through PMCs begins within 6 hours. By 24 hours, the growth of PMCs over the invaded endometrium is well established. There is evidence that attachment of endometrial cells to PMCs grown on basement membrane (BM) preparations leads to an increased rate of invasion through the BM compared to binding to the BM alone. Following binding of ESCs and EECs to PMCs, there are alterations in gene transcription by both endometrial cells and PMCs that may contribute to endometrial invasion. This suggests that PMCs play an integral role in endometrial invasion into the peritoneum. We have developed a model that allows for quantification of endometrial invasion into the peritoneum. This model has been used to evaluate growth factors and cytokines that may increase or decrease endometrial invasiveness into the peritoneum. Elucidation of factors involved in endometrial cell-PMC attachment, and characterization of changes in both PMCs and endometrial cells following binding, will further our understanding of the genesis of the early endometriotic lesion.