Protection of the Neostriatum against Excitotoxic Damage by Neurotrophin-Producing, Genetically Modified Neural Stem Cells
Protection of the Neostriatum against Excitotoxic Damage by Neurotrophin-Producing, Genetically Modified Neural Stem Cells
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DOI：
10.1523/jneurosci.16-15-04604.1996
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发表时间：
1996-08
期刊：
影响因子：
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通讯作者：
A. Martínez-Serrano;A. Björklund
中科院分区：
文献类型：
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作者：
A. Martínez-Serrano;A. Björklund
亨廷顿病是一种进行性神经退行性疾病，影响纹状体，尤其是 GABA 能纹状体投射神经元。在本研究中，我们探索了使用产生神经生长因子（NGF）或脑源性神经营养因子（BDNF）的转基因神经干细胞系作为保护纹状体神经元在移植到纹状体后免受兴奋性毒性损伤的方法，在同一区域注射喹啉酸前1周。病变一个月后，纹状体变性、病变大小和 DARPP-32 阳性投射神经元的丧失仅受到 BDNF 分泌细胞的轻微影响，但当使用产生 NGF 的干细胞作为外源营养因子来源时，则基本上受到阻止；目标区域（黑质网状部和苍白球）的神经支配也被保留。胆碱能纹状体中间神经元（胆碱乙酰转移酶免疫反应性）受到病变影响，并被 NGF 转导细胞完全拯救。在接受了产生 NGF 的细胞移植的纹状体中，星形胶质细胞和小胶质细胞对兴奋性毒性损伤的反应大大减少。该模型中产生 NGF 的细胞移植物的普遍保护作用是在防止宿主纹状体中的细胞元件响应兴奋毒素介导的毒性发展的间接作用的背景下讨论的。我们的结论是，通过转基因神经干细胞持续供应营养因子是对抗兴奋性毒性损伤纹状体神经元变性的高效方法。
Huntington’s disease is a progressive neurodegenerative disease that affects the striatum, above all, the GABAergic striatal projection neurons. In the present study, we have explored the use of genetically modified neural stem cell lines producing nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) as a means to protect the striatal neurons against excitotoxic damage after transplantation to the striatum, 1 week before the injection of quinolinic acid into the same area. One month after the lesion, striatal degeneration, lesion size, and loss of DARPP-32-positive projection neurons were only slightly affected by the BDNF-secreting cells, but substantially prevented when NGF-producing stem cells were used as a source of exogenous trophic factor; innervation of the target fields (pars reticulata of the substantia nigra and the globus pallidus) was preserved as well. Cholinergic striatal interneurons (choline acetyltransferase-immunoreactive) were affected by the lesion and completely rescued by the NGF-transduced cells. The astroglial and microglial reactions to the excitotoxic lesion were substantially reduced in the striata, which had received transplants of NGF-producing cells. The generalized protective effects of the NGF-producing cell grafts in this model are discussed in the context of an indirect action preventing the development of toxicity mediated by cellular elements in the host striatum in response to the excitotoxin. We conclude that continuous supply of trophic factors by means of genetically modified neural stem cells represents a highly effective procedure to counteract neuronal degeneration in the excitotoxically lesioned striatum.