Reconstruction of disturbed brain function with neural stem cells from the investigation of the mechanism and induction to neuronal differentiation by trophic factor

本课题研究了胚胎干细胞（ES）源性神经干细胞（NSCs）向多巴胺（DA）能神经元的诱导分化及DA能神经元的分化机制，并为NSCs神经移植修复脑功能障碍进行了基础研究。数据总结如下：1）来自NSC的DA能分化由胎儿脑中的低生理氧（3.5%O2）或在DA耗尽的纹状体中增强的细胞因子混合物（IL-113、IL-11、LIF、GDNF）诱导。2)去铁胺（DFO）预处理可使细胞周期阻滞于G1/S期，诱导神经元分化，这与p27 β蛋白升高<kiP1>和neuroD信号通路激活有关。3)多效生长因子（PTN）、IL-1β和3.5%氧诱导的DA能分化是通过与HIF-1 α表达增强相关的机制介导的。4)对PTN是否促进移植细胞存活的问题的研究清楚地揭示了对供体细胞的PTN处理促进移植后纹状体中的细胞存活，其中大多数移植细胞接近细胞死亡，导致更好的功能恢复。

We investigate 1) how to increase of the number of dopaminergic (DAergic) neurons from embryonic stem (ES) cell-derived neural stem cells (NSCs) and 2) the mechanism of DAergic differentiation, and we also carried out basic research for neural transplantation using NSCs for the recovery of disturbed brain function. Data are summarized as follows.1) DAergic differentiation from NSCs are induced by low physiological oxygen in the fetal brain (3.5% 02) or cytokine mixture (IL-113, IL-11, LIF, GDNF) which is enhanced in DA-depleted striatum. 2) Cell cycle inhibition in G 1/S phase by the pre-treatment with deferoxamine (DFO) induced neuronal differentiation relating to prolonged p27^<kiP1> elevation and activation of the neuroD signaling pathway. 3) DAergic differentiation induced by pleiotrophin (PTN), IL-1β and 3.5% oxygen is mediated by the mechanism relating to enhanced expression of HIF-1 a. 4) Investigation for the question if PTN promotes the survival of grafted cells clearly reveals that PTN treatment to donor cells promotes cell survival in the striatum after transplantation in which most grafted cells are close to cell death, resulting in better functional recovery.