Fibrosis signaling in endometrial cells and endometriosis progression

Endometriosis is characterized by the presence of inflamed and fibrotic endometrial tissue outside the uterine cavity. In our previous study, utilizing a mouse model showed that proinflammatory factors present in peritoneal hemorrhage exacerbated inflammation at the lesion through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). To identify the role of menstruation-related factors (PGE2 and thrombin, a PAR1 agonist: P/T) on the development of endometriosis, we examined using primary endometrial stromal cells (ESCs) and epithelial cells (EECs). Treating EECs with P/T stimulated cell migration, upregulated mesenchymal markers including CXCR4, and downregulated epithelial markers. Moreover, CXCL12, a ligand for CXCR4, further increased EMT marker expression and cell migration. In ESCs, P/T or estrogen treatment resulted in increased secretion of CXCL12. RNA-seq analysis revealed that activin A was upregulated in response to P/T. Activin A, in turn, increased the expression of CTGF and mesenchymal marker genes in ESCs, leading to fibroblast to myofibroblast transdifferentiation (FMT) of ESCs. CTGF also induced the expression of fibrosis markers, indicating fibrotic changes in the lesions. In summary, P/T induces both EMT and FMT in ectopic endometrial cells derived from retrograde menstruation, associated with fibrotic changes in endometriotic lesions. Pharmacological intervention targeting P/T-induced CXCL12, activin A, and CTGF signaling may inhibit fibrosis in endometriotic lesions.