Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, México, México.
Mol Ther. 2013 Aug;21(8):1579-91. doi: 10.1038/mt.2013.78. Epub 2013 Jun 4.
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.
细胞疗法在帕金森病（PD）动物模型中的作用是通过将多巴胺（DA）神经元移植到纹状体中来实现的，而将多巴胺能细胞移植到黑质内则不能导致一致的行为恢复。促进来自黑质（SN）的多巴胺能神经元向纹状体生长的一种策略是降解抑制性成分，如软骨素硫酸盐蛋白聚糖（CSPG）。另一种方法是通过趋化剂引导 DA 轴突。Sema 3A 和 3C 增强体外胚胎干细胞（ES）细胞衍生的多巴胺能神经元的轴突生长，而 Sema 3C 也吸引它们。我们询问了将 DA 神经元移植到黑质内，结合 CSPG 的降解或 Semaphorin 3 表达细胞的移植，是否能在单侧 DA 神经元耗竭的大鼠中建立新的黑质纹状体多巴胺能通路。我们发现，在 Sema 3 处理的动物中，背侧纹状体有去极化诱导的 DA 释放，SN 到纹状体的 DA 轴突投射，以及伴随的行为改善。在接受黑质内移植联合软骨素酶 ABC 治疗的动物中，这些效果不存在，尽管观察到 CSPG 的部分降解。这些结果表明，在成年患病大脑中，Semaphorin 3 引导的多巴胺能神经元的长距离轴突生长导致行为改善是可能的。
