Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease
Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease
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DOI：
10.1523/jneurosci.21-20-08108.2001
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发表时间：
2001-10-15
影响因子：
5.3
通讯作者：
Arenas, E
中科院分区：
文献类型：
--
作者：
Åkerud, P;Canals, JM;Arenas, E
神经干细胞(NSCs)被认为是治疗神经退行性变的工具，因为它们能够产生与移植结构相适应的细胞类型。在目前的工作中，我们探索了神经干细胞稳定表达转基因和局部递送具有神经保护活性的可溶性分子的能力，如胶质细胞系衍生神经营养因子(GDNF)。能释放GDNF的神经干细胞在宿主纹状体内植入良好，整合并分化为神经元、星形胶质细胞和少突胶质细胞，并在至少4个月内保持稳定的高水平表达GDNF。在帕金森病小鼠6-羟基多巴胺模型上测试了纹状体内GDNF-NSCs移植的治疗潜力。我们发现，GDNF-NSCs阻止了黑质多巴胺能神经元的退化，并减少了这些动物的行为障碍。因此，我们的结果表明，神经干细胞在体内有效地表达治疗水平的GDNF，这表明神经干细胞被设计为释放神经保护分子来治疗神经退行性疾病，包括帕金森病。
Neural stem cells (NSCs) have been proposed as tools for treating neurodegeneration because of their capacity to give rise to cell types appropriate to the structure in which they are grafted. In the present work, we explore the ability of NSCs to stably express transgenes and locally deliver soluble molecules with neuroprotective activity, such as glial cell line-derived neurotrophic factor (GDNF). NSCs engineered to release GDNF engrafted well in the host striatum, integrated and gave rise to neurons, astrocytes, and oligodendrocytes, and maintained stable high levels of GDNF expression for at least 4 months. The therapeutic potential of intrastriatal GDNF-NSCs grafts was tested in a mouse 6-hydroxydopamine model of Parkinson's disease. We found that GDNF-NSCs prevented the degeneration of dopaminergic neurons in the substantia nigra and reduced behavioral impairment in these animals. Thus, our results demonstrate that NSCs efficiently express therapeutic levels of GDNF in vivo, suggesting a use for NSCs engineered to release neuroprotective molecules in the treatment of neurodegenerative disorders, including Parkinson's disease.