Endostatin-expressing endometrial mesenchymal stem cells inhibit angiogenesis in endometriosis through the miRNA-21-5p/TIMP3/PI3K/Akt/mTOR pathway.

Abstract

Endometriosis is a chronic inflammatory and neoangiogenic disease. Endostatin is one of the most effective inhibitors of angiogenesis. Mesenchymal stem cells (MSCs) have been investigated as compelling options for cell therapy. However, the effect and mechanism of action of endostatin-expressing endometrial MSCs (EMSCs) in endometriosis are unclear. Here, EMSCs were genetically modified to overexpress endostatin (EMSCs-Endo). A reduction in the angiogenic capacity of HUVECs was observed in vitro after treatment with EMSCs-Endo. EMSCs-Endo significantly suppressed endometriotic lesion growth in vivo. The limited efficacy was associated with suppressed angiogenesis. The miRNA-21-5p level and the levels of p-PI3K, p-mTOR, and p-Akt in HUVECs and mouse endometriotic lesions significantly decreased after treatment with EMSCs-Endo, whereas TIMP3 expression significantly increased. In summary, targeted gene therapy with EMSCs-Endo is feasible, and its efficacy in regulating endometriosis can be attributed to the inhibition of angiogenesis, suggesting that EMSCs could be used as promising vehicles for targeted gene therapy.