Induction of Gap Junctional Coupling by Secreted Factor(s) from Mesothelial Cells is Required for the Invasiveness of Endometriosis

Intercellular interactions, including gap junction intercellular coupling (GJIC), have been implicated in many invasive processes (e.g. extravasation, metastasis and oocyte implantation). Yet the role of gap junctions in endometriosis, a major invasive medical problem that affects 6–10% of women worldwide, has not been investigated. Comparisons of the expression profile of endometrial cells (ECs) from endometriosis patients and normal subjects revealed a consistent reduction in the expression levels of connexins (the protein components of gap junctions), including the most abundant isoform, Cx43. This was most notable in stromal cells as the disease progressed, but was also evident in epithelial cells. GJIC of ECs from endometriosis patients was also reduced compared to normal subjects, again most notably in stromal cells. In mimicking the endometriosis process, heterotypic interactions with mesothelial cells induced an increase in GJIC, with stromal cells from endometriosis patients showing the largest response. This enhanced coupling correlated with enhanced trafficking of Cx43 to the cell surface, and enhanced invasiveness through a mesothelial monolayer. Blocking GJIC between endometrial and mesothelial cells using either siRNA or a Cx43 specific peptide blocker dramatically reduced this enhanced invasiveness of endometriosis derived ECs, whether epithelial or stromal in origin. Finally, GJIC induction by mesothelial cells was shown to be mediated by a secreted factor, which is heat resistant and approximately 5–10K is size. This presents a unique opportunity for developing novel therapy for treating endometriosis that would prevent the formation of lesions that cause the pain and incidence of infertility associated with this widespread disease. Currently the only therapies are based on hormonal treatments that only further compromise fertility problems associated with endometriosis (representing 35% of the cases on infertility in the nation). Support or Funding Information Women's Health Initiative at UTHSA School of Medicine and CPRIT grants RP150600 and RP160844, and NIH grant UL1 TR001120 for Cores This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .