Telocyte-Derived Exosomes Provide an Important Source of Wnts That Inhibits Fibrosis and Supports Regeneration and Repair of Endometrium

Intrauterine adhesions (IUAs) are commonly caused by obstetrical and gynecological procedures or infections in women of reproductive age. These adhesions are characterized by endometrial fibrosis and the inhibition of endometrial regeneration, often leading to severe fertility problems and limited treatment options. Telocytes (TCs), a recently identified type of interstitial cell found in the female uterus, have shown potential for in vitro therapeutic applications in gynecological diseases that involve defective decidualization. This study aims to explore the role of Wnt ligands derived from TCs, carried by exosomes (Exo), in reversing fibrosis and promoting regenerative repair in the endometrium. Cellular and animal models of IUA were created using endometrial stromal cells (ESCs) and mice, followed by treatment with TC-conditioned medium (TCM) or TC-derived Exo. In the cellular model, fibrosis markers (collagen type 1 alpha 1 [COL1A1], fibronectin [FN], and α-smooth muscle actin [α-SMA]), angiogenesis (vascular endothelial growth factor [VEGF]), and pathway proteins (β-catenin) were assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting (WB), and immunofluorescence. The results showed that both TCM and TC-derived Exo provide a source of Wnt ligands that inhibit fibrosis, as evidenced by increased VEGF and β-catenin levels and decreased fibrotic markers. However, this effect was blocked when Wnt/β-catenin signaling was inhibited using XAV939 or ETC-159. In the mouse model, regeneration was assessed by examining endometrial thickness, gland count, and fibrosis area ratio, along with fibrosis markers (FN), mesenchymal-epithelial transition (MET) markers (E-cadherin, N-cadherin), and angiogenesis (VEGF, microvessel density [MVD]) through hematoxylin-eosin (HE) staining, Masson’s trichrome staining, and immunohistochemistry. The results demonstrated that treatment with TC-Exo effectively promoted endometrial regeneration by alleviating fibrosis, enhancing MET, and stimulating angiogenesis. These findings provide new evidence supporting the potential therapeutic use of TC-derived Exo in treating IUAs.