电刺激调控下的诱导多向潜能干细胞移植对缺血性卒中的神经修复作用及其Presenilin1信号机制研究

Stem cell treatment is a promising therapy for neurological curing after ischemic stroke, due to the potential of neural differentiating for damaged cell replacement, and of neural factor producing for injured cell recovery. However, the pathological niche in ischemic brain tissue induces more glial, rather than neuronal differentiation of the engrafted stem cell, which could attenuate the efficiency of the neuron replacement. To improve the neuronal differentiation, we designed this project to administrate physiological electrical field (EF) induction on the induced Pluripotent Stem Cells (iPSCs) for transplantation. According to the theory that EF stimulation is essential to the nerve system development and neuron maturity, the EF induction would promise more neuronal differentiation of the iPSCs. We further design to engraft these EF-induced iPSCs in to the middle cerebral artery occlusion model mouse brain, to investigate the improving activity of iPSCs transplantation on the neurofunctional recovery by enhanced neuronal differentiation. To explain the mechanism, we would investigate on the role of Presenilin1 in EF regulated activating balance between Notch1 and Wnt/β-Catenin signalling pathway in EF-enhanced neuronal differentiation of the engrafted NSCs. The project would provide a novel strategy of stem cell therapy for ischemic stroke, as well should shine a new light on the mechanism explain for the induced neural differentiation of stem cell.

干细胞移植能够替代缺损神经细胞、并能够产生神经因子促进损伤细胞和内环境的修复，成为修复缺血性脑卒中损伤神经功能的新方法。然而，脑缺血再灌注的病理内环境却诱导更多的移植干细胞向胶质细胞分化，削弱了对受损神经元替代治疗效果。基于文献中关于生理性电刺激能够诱导调控神经系统发育和干细胞增殖与分化的报道，本课题拟对诱导多向潜能干细胞（iPSCs）施加生理性电刺激，旨在诱导促进iPSCs向神经元分化；并将此预先电刺激的iPSCs移植进入脑缺血再灌注小鼠模型脑内，检测对脑缺血卒中损伤神经功能的修复作用；同时通过蛋白质/基因间相互作用、基因敲除/敲入等技术，探讨电刺激通过Presenilin1平衡调控Notch和Wnt/β-Catenin信号通路，进而诱导iPSCs向神经元分化的分子信号机制。预期本课题研究将为干细胞移植治疗中枢神经系统疾病提供新的预处理策略，为干细胞的神经系分化作用机制提供新的机制解释。

干细胞移植能够替代缺损神经细胞、并能够产生神经因子促进损伤细胞和内环境的修复，成为修复缺血性脑卒中损伤神经功能的新方法。然而，脑缺血再灌注的病理内环境却诱导更多的移植干细胞向胶质细胞分化，削弱了对受损神经元替代治疗效果。基于文献中关于生理性电刺激能够诱导调控神经系统发育和干细胞增殖与分化的报道，本课题对诱导多向潜能干细胞（iPSCs）施加生理性电刺激，诱导促进iPSCs向神经元分化；并将此预先电刺激的iPSCs移植进入脑缺血再灌注小鼠模型脑内，检测对脑缺血卒中损伤神经功能的修复作用；同时通过蛋白质/基因间相互作用、基因敲除/敲入等技术，探讨了电刺激通过Presenilin1、Notch和Wnt/β-Catenin信号通路，进而诱导iPSCs向神经元分化的分子信号机制。预期本课题研究将为干细胞移植治疗中枢神经系统疾病提供新颖的预处理策略，也为干细胞的神经系分化作用机制提供新的机制解释。