Human amniotic fluidic derived-extracellular vesicles enriched by miR-29 ameliorate endometrial fibrosis and promote repair of damaged endometrium in an experimental model of intrauterine adhesion.

Abstract

BACKGROUND: Intrauterine adhesions (IUAs) are defined by excessive fibrotic remodeling, failure of endometrial regeneration, and impaired fertility, and that have not yet had any effective treatment options. Human amniotic fluid-derived extracellular vesicles (hAF-EVs) have inherent regenerative potential and represent a promising platform for targeted delivery of antifibrotic microRNAs such as miR-29. METHODS: A murine IUA model was established after mechanical damage of the endometrium. Unmodified hAF-derived EVs or miR-29-enriched hAF-EVs were administered to mice. Histological and immunohistochemical methods, quantitative PCR, and fertility tests were used to determine endometrial regeneration, fibrosis, angiogenesis, and molecular fibrogenic marker expression. RESULTS: Both hAF-EVs and miR-29-enriched hAF-EVs significantly improved endometrial architecture, reduced collagen deposition, and enhanced fertility outcomes compared with untreated IUA controls. While unmodified EVs exerted robust regenerative and antifibrotic effects, miR-29 enrichment resulted in greater suppression of TGF-β/SMAD3-associated fibrogenic signaling, enhanced angiogenesis, and selective improvement in implantation-related parameters. Multiple histological results revealed similar recovery in the two EV-treated groups. CONCLUSION: hAF-derived EVs constitute an effective cell-free therapeutic strategy for attenuating fibrosis and promoting endometrial repair following intrauterine adhesions. Enrichment with miR-29 provides selective enhancement of molecular and functional outcomes, supporting its role as a targeted modulatory component within an EV-based regenerative platform.