Extracellular Vesicles Derived From Endometrial Stem Cells Preconditioned With PGE2-Reverse Myofibroblast Phenotype in Mare Endometrial Cells: A Novel Anti-Fibrotic Approach.

Endometrial fibrosis in mares compromises fertility through aberrant extracellular matrix deposition and sustained myofibroblast activation. Conventional interventions fail to reverse these pathological alterations, necessitating innovative, mechanism-focused therapies. In this study, we pioneered the use of prostaglandin E2 (PGE2) preconditioning of equine endometrial-derived mesenchymal stem cells (ET-eMSCs) and their extracellular vesicles (EVs) to target fibrotic processes directly. ET-eMSCs were isolated from mare endometrial biopsies pretreated with PGE2 to enhance their anti-fibrotic secretome, and EVs were subsequently harvested. In vitro assays demonstrated that PGE2-preconditioned ET-eMSCs and their EVs inhibited α-smooth muscle actin expression, reduced collagen I deposition, and restored key endometrial markers of receptivity and proliferation. These findings establish the first evidence that PGE2-enhanced ET-eMSC-derived EVs can exert anti-fibrotic effects in an in vitro model of equine endometrial fibrosis. This study provides a robust translational framework for developing targeted regenerative therapies for fibrotic diseases across species, with potential applications in human reproductive medicine.