诱导性多能干细胞源性MSCs通过线粒体输送对心跳骤停后脑损伤的保护

项目名称： 诱导性多能干细胞源性MSCs通过线粒体输送对心跳骤停后脑损伤的保护

项目编号： No.81471832

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李欣

作者单位： 广东省人民医院

项目金额： 72万元

中文摘要： 线粒体结构功能障碍以及因此而致的能量匮乏是导致心跳骤停(CA)后脑损伤的核心环节，目前尚无针对此靶点的有效措施。骨髓间充质干细胞（MSC）可通过Cx43蛋白形成的连接通道向上皮细胞转移线粒体而减轻肺损伤。我们报道了诱导性多能干细胞（iPSC）来源的MSC可显著提高CA大鼠的脑功能。我们还发现iPSC-MSC与神经细胞间可形成连接通道并输送线粒体、抑制凋亡；而起桥梁作用的正是Cx43。因此我们设想iPSC-MSC可通过线粒体输注的方式向受损细胞提供新鲜线粒体而防治脑损伤，而上调Cx43可强化此作用。本课题拟通过细胞共培养和大鼠CA模型，观察iPSC-MSC能否发挥输送新鲜线粒体、恢复能量代谢、拮抗氧化应激、改善脑功能的作用；并转染Cx43以寻求更有效的干细胞治疗技术。iPS是个突破性的科学发现，iPSC-MSCs具有强大应用优势，本研究有助阐明其脑保护的作用机制，并为其临床应用提供依据。

中文关键词： 心跳骤停；脑损伤；诱导性多能干细胞；线粒体；缝隙连接蛋白

英文摘要： Mitochondrial dysfunction and energy deficiency resulted from it play an important role in the cerebral injury after cardiac arrest(CA). However, there is no effective treatment to promote cerebral function via improving the function of mitochondria. Bone marrow derived mesenchymal stem cells (MSC) protect against acute lung injury by mitochondrial transfer to injured epithelial cells through Cx43-dependent gap junctional channels. Recently, MSC was succefully induced from induced pluripotent stem cell (iPSC). We found that iPSC-MSC significantly improved cerebral function in a rat model of CA. Furthermore, using coculture model of iPSC-MSC and neuroal cell line, we observed formation of tunneling nanotubes (TNTs) between MSC and neuroal cell, and there was exchange of mitochondria between two types of cells via TNTs. In which, Cx43 played the important role. We next hypothesize that (1) iPSCMSC has the potential to protect neurons via transfering fresh mitochondrias after CA; (2) Cx43 transfection to iPSC-MSC improves the above effects. In this project, we induce a coculture model of iPSC-MSC and neuronal cell line and primary neurons and a rat model of CA. We aim to investigate whether Ipsc-MSC transports the fresh mitochondrias, recovers energy metabolism,inhibits oxidative stress and promotes cerebral function; to examine whether Cx-43-transfected iPSC-MSC improves the above effects and further prevents cerebral function. The scientist who first reported iPS won the Nobel Prize in Physiology or Medicine in 2012. This study is timely and may provide useful information to the mechanism of neuroprotection of iPSCMSC on cerebral injury after CA.

英文关键词： Cardiac arrest;Cerebral injury;Induced pluripotent stem cells;Mitochondria;Connexin