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)-β 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)-α, 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 β-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-α, TGF-β, 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.