Endometrial regeneration with mesenchymal stem cells and exosomes: an experimental rat model of intrauterine adhesions

Intrauterine adhesions (IUA) arise from inflammation-driven fibrotic remodeling that limits endometrial repair. Mesenchymal stem cells (MSCs) and MSC-derived exosomes are promising, but direct comparisons by tissue source and delivery route are limited. To compare umbilical cord (UC) and adipose-derived MSCs versus their exosomes and to assess local intrauterine versus intravenous (IV) UC-exosome delivery in a rat IUA model. Thirty-five female Sprague-Dawley rats were randomized (n = 5/group) to negative control, positive control (ethanol-IUA), and five treatment arms (local UC-MSC, UC-Exo, Adipose-MSC, Adipose-Exo, and IV UC-Exo). IUA was induced with 0.3 mL 95% ethanol; treatments were administered 2 weeks later. Two weeks after treatment, uterine tissues underwent H&E/Masson's trichrome evaluation, epithelial and wall thickness measurements, and blinded 0-3 scoring of inflammation, vascular proliferation, and fibrosis. Positive controls showed severe fibrosis and luminal narrowing. All treated groups demonstrated improved architecture and reduced collagen deposition versus positive controls. Epithelial thickness was higher in treated groups but did not differentiate treatment arms; only negative vs. positive controls differed (p < 0.001). Uterine wall thickness increased in all treatment groups versus positive controls (overall p < 0.006), and local and IV UC-Exo groups were similar. Remodeling scores (inflammation/fibrosis) separated groups more clearly, with the most favorable combined profile in the Adipose-Exo group. MSC-based interventions (especially exosomes) attenuated inflammatory-fibrotic remodeling in this rat IUA model. Tissue source and product type influenced the repair profile while IV exosome delivery produced remodeling effects comparable to local administration.