neural stem cell transplantation for the Parkinson's disease

为了利用神经干细胞实现帕金森病(PD)的脑内细胞替代治疗，我们假设使用神经干细胞(NSCs)自体移植是最安全和最有效的治疗方法之一。我们的研究表明：首先，从成年啮齿动物或灵长类动物的脑室下区获取神经干细胞，在增殖因子的存在下扩增到可移植的细胞数量，并利用酪氨酸羟化酶诱导因子将其分化为大量的多巴胺能神经元。第二，成年NSCs移植具有神经保护作用，包括行为和组织学改善。其机制是成体神经干细胞能够分泌多种神经营养因子和细胞因子(神经营养因子、促红细胞生成素、神经营养因子等)，对移植的纹状体周围有影响。第三，建立了对多巴胺能神经元具有最强神经营养作用的神经干细胞之一，产生神经干细胞(NSC-G…More DNF)采用GDNF基因转染法。移植NSC-GDNF对帕金森病模型动物具有神经保护作用，表现为行为学和组织学的改善。NSC-GDNF分泌的GDNF对移植细胞和移行细胞也有较强的存活和迁移作用。其机制是移植NSC-GDNF可改变受损纹状体的微环境，宿主神经胶质细胞可释放除GDNF外的其他营养因子。最后，移植成年NSC来源的多巴胺能神经元对帕金森病大鼠模型具有修复作用。移植的神经干细胞来源的DA神经元在损毁的纹状体中存活较差，但移植的DA神经元与宿主神经元之间有大量的突触形成。其机制可能是上调BDNF和磷酸化CREB，促进突触生成，提示成人神经干细胞自体移植在帕金森病的治疗中是有用的。较少

For Parkinson's disease (PD) to realize intracerebral cell replacement therapy using neural stem cells, we hypothesized that autologous transplantation using neural stem cells (NSCs) is one of the safest and most useful therapies.We showed the following:First, neural stem cells were harvested from the subventricular zone of adult rodents or primates, were expanded to the transplantable number of cells in the presence of proliferating factors, and could be differentiated into a large number of dopaminergic neurons using tyrosine hydroxylase-inducing factor.Second, transplantation of adult NSCs had the neuroprotective effects as the behavioral and histological improvements. The mechanism is that adult NSCs could secrete the various kinds of neurotrophic factors and cytokines (GDNF, EPO, CNTF etc), which had the effects surrounding to the transplanted striatum.Third, We established the GDNF, which has a one of the most neurotrophic effect on the dopaminergic neurons, producing NSCs (NSC-G … More DNF) using GDNF gene transfection method. The transplantation of NSC-GDNF had a neuroprotective effect in the parkinsonian model animals as the behavioral and histological improvements. GDNF secreted from NSC-GDNF also had a strong surviving and migrating effect for the grafted cells and migrating. The mechanism is that NSC-GDNF transplantation may change the microenvironment into the lesioned striatum and the accommodated host glial cells may release the other trophic factors except for GDNF.Finally, transplantation of dopaminergic (DA) neurons derived from adult NSCs has a restorative effect for the parkinsonian rat model. The survival of the grafted DA neurons derived from NSCs was poor in the lesioned striatum, but the great number of synapse formation between the grafted DA neurons and host neurons were observed. The mechanism is that upregulation of BDNF and phosphorylated CREB may enhance the synaptogenesis.These results suggested that autologous transplantation of adult neural stem cells is useful in the treatment of PD. Less