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

我们研究了1)如何从胚胎干细胞（ES）衍生的神经干细胞（NSCs）中增加多巴胺能（DAergic）神经元的数量和2)DAergic分化的机制，并开展了利用NSCs进行神经移植以恢复脑功能紊乱的基础研究。数据汇总如下：1)胚胎脑低生理氧（3.5% - 02）或细胞因子混合物（IL-113、IL-11、LIF、GDNF）在缺da纹状体中增强，可诱导NSCs的能分化。2)去铁胺（DFO）预处理对g1 /S期细胞周期的抑制诱导神经元分化，与延长p27^<kiP1>升高和激活神经d信号通路有关。3)多营养因子（PTN）、IL-1β和3.5%氧诱导的DAergic分化与HIF-1表达增强有关。4)对PTN是否促进移植物细胞存活的研究清楚地表明，PTN处理供体细胞促进移植后纹状体细胞存活，移植物细胞大部分接近死亡，功能恢复较好。

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.