Institute of Neurosciences, The Fourth Military Medical University, Xi'an, 710032, P.R. China.
CNS Neurol Disord Drug Targets. 2011 Jun;10(4):517-28. doi: 10.2174/187152711795563912.
Parkinson's disease (PD) is a severe deliberating neurological disease caused by progressive degenerative death of dopaminergic neurons in the substantia nigra of midbrain. While cell replacement strategy by transplantation of neural stem cells and inducement of dopaminergic neurons is recommended for the treatment of PD, understanding the differentiation mechanism and controlled proliferation of grafted stem cells remain major concerns in their clinical application. Here we review recent studies on molecular signaling pathways in regulation of dopaminergic differentiation and proliferation of stem cells, particularly Wnt/beta-catenin signaling in stimulating formation of the dopaminergic phenotype, Notch signaling in inhibiting stem cell differentiation, and Sonic hedgehog functioning in neural stem cell proliferation and neuronal cell production. Activation of oncogenes involved in uncontrolled proliferation or tumorigenicity of stem cells is also discussed. It is proposed that a selective molecular manipulation targeting strategy will greatly benefit cell replacement therapy for PD by effectively promoting dopaminergic neuronal cell generation and reducing risk of tumorigenicity of in vivo stem cell applications.
帕金森病（PD）是一种严重的进行性神经退行性疾病，由中脑黑质多巴胺能神经元进行性退化死亡引起。虽然移植神经干细胞和诱导多巴胺能神经元的细胞替代策略被推荐用于治疗 PD，但在其临床应用中，了解移植干细胞的分化机制和受控增殖仍然是主要关注点。在这里，我们回顾了近年来关于调控干细胞多巴胺能分化和增殖的分子信号通路的研究，特别是 Wnt/β-catenin 信号通路在刺激多巴胺能表型形成中的作用、Notch 信号通路在抑制干细胞分化中的作用以及 Sonic hedgehog 在神经干细胞增殖和神经元生成中的作用。还讨论了涉及干细胞不受控制增殖或致瘤性的癌基因的激活。有人提出，通过有效促进多巴胺能神经元生成和降低体内干细胞应用致瘤性风险，针对特定分子的操纵靶向策略将极大地有益于 PD 的细胞替代治疗。
