Umbilical Cord Mesenchymal Stem Cells‐Derived Exosomes Promote the Repair of Endometrial Injury via the miR‐21‐5p/PTEN/AKT Axis

Background: Endometrial injury contributes to the reduction of endometrial receptivity and is widely recognized as a critical factor in implantation failure. Increasing evidence suggests that the therapeutic effects of mesenchymal stem cells (MSCs) mainly depend on their capacity to secrete paracrine factors specifically MSC‐derived exosomes (MSC‐Exos), which are regulated by exosomal miRNA. In this study, we investigated the effects of human umbilical cord MSC‐Exos (hUCMSC‐Exos) on injured endometrium and the potential mechanisms. Methods: To observe the distribution of exosomes in vivo, DIR‐labeled hUCMSC‐Exos were injected into the tail vein of endometrium‐injured mice. The recovery of mice damaged endometrium after exosome treatment was detected by hematoxylin–eosin (HE), TUNEL staining, and immunohistochemistry. Then, western blot measured the expression of Bcl‐2, Bax, and cleaved caspase‐3. The mRNA expression of vascular endothelial growth factor (VEGF) and insulin‐like growth factor‐1 (IGF‐1) was evaluated by quantitative real‐time PCR (qRT‐PCR). Furthermore, miR‐21‐5p was checked in mifepristone‐injured endometrial stromal cells (EndoSC) after the hUCMSC‐Exos addition. The cell viability and apoptosis were analyzed and phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/serine/threonine kinase (AKT) pathway were confirmed with hUCMSC‐Exos transfected the miR‐21‐5p. Results: hUCMSC‐Exos migrated to the damaged endometrium, and the endometrial thickness, the number of glands as well as embryo implantation rate were significantly increased ( p < 0.05). hUCMSC‐Exos could inhibit apoptosis in our mouse endometrial injury model. Besides, the expression of Ki67 and cluster of differentiation 31 (CD31) was significantly increased ( p < 0.05). The VEGF and IGF‐1 expression was significantly upregulated in the exosome group ( p < 0.05). The repair effect of exosomes on damaged cells was further enhanced after transfection with miR‐21‐5p mimics and counteracted after transfection with inhibitors. The repair of damaged cells is related to decreased PTEN level and activated the PI3K/AKT signaling pathway. Conclusion: hUCMSC‐Exos ameliorated the damaged uterus, increased the number of glands and embryo implantation rates, suppressed apoptosis, and improved the cell proliferation in the mouse injured endometrium model. Exosomal miR‐21‐5p positively regulated the repair of endometrial injury and enhances the therapeutic effect of hUCMSC‐Exos by activate the PTEN/AKT signaling pathways.