Exosomes Derived from Umbilical Cord Mesenchymal Stem Cells Promote Repair of Damaged Endometrium by Activating PTEN/AKT Pathway

Abstract Background: Endometrial injury contributes to impaired endometrial receptivity, and is well 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 and are mediated by MSC-derived exosomes (MSC-Exos). In this study, we investigated the effects of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) on injured endometrium in the mouse endometrial damage model and the potential mechanisms.Methods: All female mice were randomly divided into control group, saline group, and exosome (Exo) group. To observe the distribution of exosomes in vivo, DiR-labeled hUCMSC-Exos were injected into the tail vein of endometrium-injured mice. HE staining was used to detect changes in endometrial thickness and number of glands. Fertility recovery of the uterus was measured by testing embryo implantation rates. TUNEL staining was used to detect cells apoptosis. The expression of Ki67 and CD31 was examined by immunohistochemistry. Then, western blotting was used to measure the expression of Bcl-2, Bax, Cleaved Caspase-3, PTEN, AKT and p-AKT. The mRNA expression of VEGF and IGF-1 was detected by RT-PCR.Results: hUCMSC-Exos was able to migrate to the damaged endometrium. After hUCMSC-Exos injection, the endometrial thickness, the number of glands and embryo implantation rate were significantly increased (P< 0.05). Compared with the saline group, apoptosis was significantly reduced in the exosome group, and the expression of Ki67 and CD31 was significantly increased (P< 0.05). Besides, the expression of Bax, Cleaved Caspase-3 and PTEN was reduced as hUCMSC-Exos addition, and the Bcl-2 and p-AKT expression was increased. The expression of VEGF and IGF-1 was significantly up-regulated in the exosome group compared to the saline group (P< 0.05). Conclusions: 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. Furthermore, we discovered that hUCMSC-Exos could activate the PTEN/AKT signaling pathways and induce the overexpression of VEGF and IGF-1 in vivo.