Xiang Sun1, Long-Hua Luo2, Liang Feng2, Dong-Shui Li2. 1. Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, People's Republic of China. Electronic address: tao52983249@163.com. 2. Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, People's Republic of China.
Abstract
AIMS: In the treatment of diabetes mellitus associated erectile dysfunction (DMED), the intracavernous and periprostatic implantations of bone marrow derived mesenchymal stem cells (BM-MSCs) represent the new therapeutic approaches with great applied prospect. However, the specific mechanisms of BM-MSCs protecting erectile function remain largely unknown. MATERIALS AND METHODS: The DMED rats were induced and the erectile function was assessed in the models with or without BM-MSCs implantation using intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio. The differentiation of BM-MSCs toward endothelial cells (ECs) was induced by exogenous vascular endothelial growth factor (VEGF) in vitro. RNA pull-down and RIP assays were performed to explore the interaction between MEG3 and FOXM1 protein. KEY FINDINGS: Intracavernous implantation of BM-MSCs effectively improved the erectile function of DMED rats, which was accompanied by a significant decrease in the expression of MEG3 in the corpus cavernosum tissues. Also, our study revealed that MEG3 expression was significantly down-regulated during the endothelial differentiation of BM-MSCs in vitro. The down-regulation of MEG3 was further confirmed to be conducive to the differentiation of BM-MSCs toward ECs. More importantly, MEG3 promoted the degradation of FOXM1 protein via facilitating FOXM1 ubiquitination, thereby decreasing VEGF expression, which ultimately regulated the endothelial differentiation of BM-MSCs. SIGNIFICANCE: Taken together, our findings presented the vital role of MEG3 in the repairing processes of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSCs-mediated DMED repairing.
AIMS: In the treatment of diabetes mellitus associated erectile dysfunction (DMED), the intracavernous and periprostatic implantations of bone marrow derived mesenchymal stem cells (BM-MSCs) represent the new therapeutic approaches with great applied prospect. However, the specific mechanisms of BM-MSCs protecting erectile function remain largely unknown. MATERIALS AND METHODS: The DMEDrats were induced and the erectile function was assessed in the models with or without BM-MSCs implantation using intracavernous pressure (ICP)/mean arterial pressure (MAP) ratio. The differentiation of BM-MSCs toward endothelial cells (ECs) was induced by exogenous vascular endothelial growth factor (VEGF) in vitro. RNA pull-down and RIP assays were performed to explore the interaction between MEG3 and FOXM1 protein. KEY FINDINGS: Intracavernous implantation of BM-MSCs effectively improved the erectile function of DMEDrats, which was accompanied by a significant decrease in the expression of MEG3 in the corpus cavernosum tissues. Also, our study revealed that MEG3 expression was significantly down-regulated during the endothelial differentiation of BM-MSCs in vitro. The down-regulation of MEG3 was further confirmed to be conducive to the differentiation of BM-MSCs toward ECs. More importantly, MEG3 promoted the degradation of FOXM1 protein via facilitating FOXM1 ubiquitination, thereby decreasing VEGF expression, which ultimately regulated the endothelial differentiation of BM-MSCs. SIGNIFICANCE: Taken together, our findings presented the vital role of MEG3 in the repairing processes of BM-MSCs for erectile function and provided new mechanistic insights into the BM-MSCs-mediated DMED repairing.