MSCs修复糖尿病血管内皮细胞线粒体损伤的作用及机制

糖尿病血管病是糖尿病主要并发症之一，其新型治疗手段的研究是目前临床研究的热点。糖脂毒性引起的血管内皮细胞ROS堆积，线粒体损伤，NO生物利用度降低是导致该细胞失功，引起心血管病变的重要原因。大量实验已证明间充质干细胞（MSCs）对心肌梗死、缺血性血管病等心血管疾病有良好治疗作用。近年来研究发现MSCs细胞通过在细胞间形成隧道纳米管结构，介导线粒体向损伤靶细胞转移是MSCs修复靶细胞损伤的新机制。但其对血管内皮细胞的修复机制还有待深入研究。本课题将通过建立人脐静脉内皮细胞模型和糖尿病肾病大鼠模型，系统研究MSCs调节糖尿病血管内皮细胞能量代谢紊乱的分子机制；通过分子影像定位技术，揭示线粒体转移在MSCs修复糖尿病内皮细胞损伤中的机制；以前期SIRT1分子相关信号通路研究发现为线索，深入研究并阐明MSCs调节靶细胞线粒体功能的分子机制。为MSCs在糖尿病血管病中的应用提供科学依据。

Diabetic artery disease is one of the important diabetes complications, characterized by poor therapeutic outcome and high mortality. Development of new therapeutic strategies for diabetic artery disease is essential for the clinical treatment. In diabetic condition, glucolipotoxicity, caused by high levels of glucose and lipids in circulation, profoundly increases the accumulation of superoxide anion and lipid peroxide in endothelial cells. The excessive ROS is capable to impair mitochondrial biogenesis, reduce NO production and damage the NO homeostasis, leading to endothelial dysfunction and subsequent various cardiovascular diseases. Mesenchymal Stem Cells (MSCs) are multipotent non-hematopoietic stem cells that have the capacity for self-renewal and terminal differentiation into a multitude of different cell types. Due to their paracrine, transdifferentiation, and immunosuppresive effects, MSCs hold great promise as therapy for cardiovascular disease, such as myocardium regeneration and ischemic vascular disease. Recent studies discovered that intercellular communication using tunnneling nanotubes (TNT) can transfer mitochondria between MSCs and target cells, which is considered as a new machinary for the therapeutic function of MSCs. Nevertheless, the precise mechanism involved in the rescue of endothelia cells by MSCs is still to be elucidate. . Our previous study showed that high glucose level induced endothelial damage, and MSCs protected the endothelial cells from it by rescuing mitochondrial function and cell viability, and reducing ROS production. Additionally, we found that the machinery was relevant to the SIRT1 signaling pathway. Based on these results, we will establish human umbilical vein endothelial cell (HUVEC) model and rat diabetic nephropathy model to in depth investigate the regulation of energetic metabolism of diabetic endothelium by MSCs; discover the role of mitochondrial transferring in MSCs mediated endothelial rescue; and elucidate the molecular mechanism in regulation of mitochondrial function by MSCs focusing on SIRT1 signaling pathway. Our project will shed light to the clinical treatment of MSCs on diabetic vascular disease.