HIF-2α-BMSCs携载TLR4-siRNA纳米颗粒治疗缺血性脑损伤的机制研究

Stem cells can promote angiogenesis and protect dying neurons in the penumbra, which has become a focus of the treatment of ischemic brain injury. However, inflammatory injury microenvironment, as a "bottleneck", has a significant inhibitory effect on the survival of the stem cells in the penumbra. Our previous studies have demonstrated that HIF-2α-BMSCs can differentiate into endothelial cells, promote angiogenesis and home to the penumbra. We hypothesize that nanoparticles harbouring TLR4-siRNA constructed might be transported to the penumbra by HIF-2α-BMSCs to treat ischemic brain injury. The purpose of this research program to determine the relationship between the promotion of angiogenesis and inhibition of inflammatory injury, the number and distribution of HIF-2α-BMSCs and TLR4-siRNA nanoparticles in the penumbra, which is very conducive to analyse the relationship between protecting dying neurons and improving neurological function. It is very important for providing new materials and technology for optimizing stem cell transplantation in the treatment of ischemic brain injury.

干细胞能够促进半暗带血管新生并保护濒死神经元，是治疗缺血性脑损伤的研究热点。然而，半暗带的炎症损伤微环境是限制其应用的 "瓶颈"。Toll样受体4(Toll like receptors，TLR4)是介导半暗带炎症损伤和细胞凋亡的重要分子。我们已证实：过表达缺氧诱导因子-2α的BMSCs (HIF-2α-BMSCs) 向内皮细胞分化和促进血管新生的能力明显增加，并能靶向聚集在半暗带。本项目拟构建TLR4-siRNA纳米颗粒，在HIF-2α-BMSCs促进血管新生的基础上，以HIF-2α-BMSCs为载体将TLR4-siRNA纳米颗粒运输到半暗带；观察HIF-2α-BMSCs和 TLR4-siRNA纳米颗粒在半暗带的数量和分布，分析其与促进血管新生和抑制炎症损伤的关系并探讨机制，分析其与保护半暗带濒死神经元和改善神经功能的关系并探讨机制，为优化干细胞移植治疗缺血性脑损伤提供新材料和新技术。