Fibrosis signaling in endometrial cells and endometriosis development

Abstract

In endometriosis, the tissues similar to the endometrial tissue attaches outside the uterine cavity, causing inflammation and fibrosis. The retrograde menstruation theory is the most plausible mechanism, though the detailed pathogenesis remains unclear. Our observations suggest that endometriosis-like lesions occur more often at sites of ovarian excision causing bleeding in mouse models. Additionally, prostaglandin E2 (PGE2) and thrombin, a protease-activated receptor (PAR) agonist in menstrual blood exacerbate inflammation in these lesions. Focusing on the hypoxic conditions of menstrual blood, we investigated the effects of PGE2/thrombin on inflammation and fibrosis using primary cultured endometrial stromal cells (ESCs) and glandular epithelial cells (EECs) under low oxygen conditions. Chemokine CXCL12 secreted by endometrial stromal cells under hypoxia acts on CXCR4 receptors on glandular epithelial cells, inducing epithelial-mesenchymal transition (EMT), suggesting a possible role in endometriosis progression. RNA-seq analysis of PGE2/thrombin effects on endometrial stromal cells revealed activation of the transforming growth factor (TGF)-β pathway, particularly increased production and secretion of activin A, a member of the TGFβ family. Activin A, via increased connective tissue growth factor (CTGF) expression, promotes differentiation of endometrial stromal cells from fibroblast-like to myofibroblast transdifferentiation (FMT) of ESCs. In conclusion, targeting the CXCL12/CXCR4 and activin A/CTGF signaling pathways holds promise for improving fibrosis in endometriosis lesions.