Recovery From Experimental Parkinsonism by Semaphorin-guided Axonal Growth of Grafted Dopamine Neurons
Recovery From Experimental Parkinsonism by Semaphorin-guided Axonal Growth of Grafted Dopamine Neurons
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DOI：
10.1038/mt.2013.78
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发表时间：
2013-08-01
影响因子：
12.4
通讯作者：
Velasco, Ivan
中科院分区：
文献类型：
--
作者：
Emmanuel Diaz-Martinez, N.;Tamariz, Elisa;Velasco, Ivan
帕金森病（PD）动物模型中的细胞治疗在纹状体内移植多巴胺（DA）神经元后是有效的，而黑质内移植多巴胺能细胞不会引起一致的行为恢复。促进多巴胺能神经元从黑质（SN）到纹状体的轴突生长的一种策略是降解抑制性组分如硫酸软骨素蛋白聚糖（CSPG）。另一种选择是通过向化剂引导DA轴突。Semaphorin 3A和3C在体外促进胚胎干细胞（ES）衍生的多巴胺能神经元的轴突生长，而Semaphorin 3C也吸引它们。我们问是否黑质内移植的DA神经元，结合CSPG的降解或与移植物的Semaphorin 3表达细胞，对纹状体，是有效的，在建立一个新的黑质纹状体多巴胺能通路与单方面消耗的DA神经元的大鼠。我们发现去极化诱导的DA释放在背侧纹状体，DA轴突的预测从SN纹状体，并伴随行为改善Semaphorin 3治疗的动物。在接受黑质内移植联合软骨素酶ABC治疗的动物中不存在这些作用，尽管观察到CSPG部分降解。这些结果证明，脑信号蛋白3指导多巴胺能神经元的长距离轴突生长，导致行为改善，在成人患病大脑中是可能的。
Cell therapy in animal models of Parkinson's disease (PD) is effective after intrastriatal grafting of dopamine (DA) neurons, whereas intranigral transplantation of dopaminergic cells does not cause consistent behavioral recovery. One strategy to promote axonal growth of dopaminergic neurons from the substantia nigra (SN) to the striatum is degradation of inhibitory components such as chondroitin sulphate proteoglycans (CSPG). An alternative is the guidance of DA axons by chemotropic agents. Semaphorins 3A and 3C enhance axonal growth of embryonic stem (ES) cell-derived dopaminergic neurons in vitro, while Semaphorin 3C also attracts them. We asked whether intranigral transplantation of DA neurons, combined with either degradation of CSPG or with grafts of Semaphorin 3-expressing cells, towards the striatum, is effective in establishing a new nigrostriatal dopaminergic pathway in rats with unilateral depletion of DA neurons. We found depolarization-induced DA release in dorsal striatum, DA axonal projections from SN to striatum, and concomitant behavioral improvement in Semaphorin 3-treated animals. These effects were absent in animals that received intranigral transplants combined with Chondroitinase ABC treatment, although partial degradation of CSPG was observed. These results are evidence that Semaphorin 3-directed long-distance axonal growth of dopaminergic neurons, resulting in behavioral improvement, is possible in adult diseased brains.