Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model

Background: Mesenchymal stem cells (MSCs) have diverse functions in regulating injury and inflammation through the secretion of extracellular vesicles (EVs). Methods: In this study, we investigated the systemic administration of extracellular vesicles derived from human umbilical cord mesenchymal stem cells (UCMSCs-EVs) as a therapeutic agent for intrauterine adhesions (IUAs) caused by endometrial injury. Additionally, we investigated the therapeutic impact of both UCMSCs-EVs and estrogen either separately or in combination in a rat model. The inflammation, vascularization, proliferation, and extent of fibrosis were assessed by a histopathological and immunohistochemical assessment using transforming growth factor (TGF)-beta as a fibrotic marker and vascular endothelial growth factor (VEGF) as a vascular marker. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6 (inflammatory cytokines), CD140b (a marker of endometrial stem cells), and RUNX2 (an antifibrotic factor). Finally, Western blotting was used to evaluate collagen I and beta-actin expression. Results: The therapeutic groups treated with either UCMSCs-EVs alone or combined with estrogen exhibited a significant decrease in inflammation and fibrosis (TNF-alpha, TGF-beta, IL-1, IL-6, RUNX2, and collagen-I) as well as a significant decrease in vascularization (VEGF) compared with the untreated rats with IUAs. The most significant results were obtained in animals with IUAs that received a combined therapy of UCMSCs-EVs and estrogen. Conclusions: We conclude that the synergistic action of human UCMSCs-EVs combined with estrogen provides a highly effective alternative regenerative agent in IUA treatment.