Endometrial stem cells repair injured endometrium and induce angiogenesis via AKT and ERK pathways

Intrauterine adhesions are common acquired endometrial syndromes secondary to endometrial injury, with limited effective therapies. Recently, several studies have reported that bone marrow stem cells (BMSCs) could repair injured endometrium in animal experiments. However, the role of stem cells in endometrial injury repair and its therapeutic mechanisms remain unclear. Here, we established mouse endometrial injury model and examined the benefit of human endometrial mesenchymal stem cells derived from menstrual blood (MenSCs) in restoration of injured endometrium. Injured endometrium exhibited significantly accelerated restoration at Day 7 after MenSCs transplantation, with increased endometrial thickness and microvessel density. Moreover, the fertility of mice with injured endometrium was improved, with higher conception rate (53.57% vs 14.29%, P = 0.014) and larger embryo number (3.1 +/- 0.6 vs 0.9 +/- 0.7, P = 0.030) in MenSCs group than control group, while no difference was found in undamaged horns between two groups. Conditioned medium from MenSCs (MenSCs-CM) could decrease H2O2-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and promote proliferation, migration and angiogenesis. Angiogenesis effect of MenSCs-CM was also confirmed in Matrigel plug assay in mice. Furthermore, we discovered that MenSCs-CM could activate AKT and ERK pathways and induce the overexpression of eNOS, VEGFA, VEGFR1, VEGFR2 and TIE2 in HUVECs, which are critical in MenSCs-CM-induced angiogenesis. Angiogenesis induced by MenSCs-CM could be reversed by inhibitors of AKT and/or ERK. Taken together, we concluded that MenSCs could restore injured endometrium and improve the fertility of the endometrial injury mice, which was partially attributed to angiogenesis induced by MenSCs.