Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, People's Republic of China.
Department of Urology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, People's Republic of China.
Life Sci. 2018 Sep 1;208:246-252. doi: 10.1016/j.lfs.2018.07.024. Epub 2018 Aug 10.
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.
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.
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.
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.
在治疗糖尿病相关勃起功能障碍（DMED）中，骨髓间充质干细胞（BM-MSCs）的海绵体内和前列腺周围植入代表了具有广阔应用前景的新治疗方法。然而，BM-MSCs 保护勃起功能的确切机制在很大程度上仍不清楚。
通过海绵体压/平均动脉压（ICP/MAP）比值评估有无 BM-MSCs 植入的 DMED 大鼠模型中的勃起功能。体外通过外源性血管内皮生长因子（VEGF）诱导 BM-MSCs 向内皮细胞（ECs）分化。通过 RNA 下拉和 RIP 实验探索 MEG3 和 FOXM1 蛋白之间的相互作用。
BM-MSCs 海绵体内植入可有效改善 DMED 大鼠的勃起功能，同时伴有海绵体组织中 MEG3 表达的显著降低。此外，我们的研究表明，BM-MSCs 体外向 ECs 分化过程中 MEG3 表达显著下调。MEG3 的下调进一步证实有利于 BM-MSCs 向 ECs 的分化。更重要的是，MEG3 通过促进 FOXM1 泛素化促进 FOXM1 蛋白的降解，从而降低 VEGF 表达，最终调节 BM-MSCs 的内皮分化。
综上所述，我们的研究结果表明 MEG3 在 BM-MSCs 修复勃起功能的过程中发挥重要作用，并为 BM-MSCs 介导的 DMED 修复提供了新的机制见解。
