Development of a new regenerative treatment for Parkinson's disease by way of inducing proliferation, migration, and differentiation of neural stem cells in situ

成年小鼠脑中有两个神经发生区，其中包含神经干/祖细胞(NSPC)。它们可以分化为神经细胞、星形胶质细胞和少突胶质细胞。最近的研究表明，脑室下区的神经干细胞向侧脑室发出延伸并接受信号。帕金森氏症是一种神经退行性疾病，可以通过提供多巴胺来改善症状来治疗，但这不是根治方法。迟早，多巴胺能神经元退化，不能产生多巴胺，导致症状恶化。胎儿黑质组织移植可以作为根治性治疗的候选方法之一，但由于伦理问题和难以获得足够数量的此类组织而不被视为标准方法。ES细胞和iPS细胞可以分化为多巴胺能细胞，但在应用于人类之前，必须控制分化的程度和偶尔发生的肿瘤。免疫排斥…必须控制更多的电子反应和道德问题。黑质纹状体束神经元的退化耗尽纹状体多巴胺，导致帕金森氏症。纹状体位于侧脑室附近，提示脑室下神经干细胞通过促进增殖、迁移和分化而成为治疗本病的良好候选细胞。在目前的项目中，我们研究了Eph/eaffin信号系统是否可以用于治疗大鼠和绒猴的帕金森病。在大鼠，侧脑室注射聚集性eaffin-A1可诱导NSPC的增殖、向多巴胺能神经元迁移和分化，以及纹状体内血管生成。这些作用可改善一侧黑质纹状体损毁大鼠的行为。组织学和行为学改善持续至少12周。Marmosettes的脑室如此之小，以至于很难向侧脑室注射成簇的eaffin-A1。然而，根据Supermex的测量，在侧脑室内和侧脑室周围多次注射肾上腺素-A1改善了动物的行为。在大肠杆菌中表达了融合有软骨低聚基质蛋白卷曲卷曲结构域的重组ePhin-A1，但产物不溶于水，可能是由于形成了大的多聚体所致。由于这些结果，我们使用了用抗Ig G(Fc)抗体对ePhin-A1-Fc进行聚类的真实方法。较少

Adult mouse brain has two neurogenic areas that contain neural stem/progenitor cells (NSPC). They can differentiate to nerve cells, astrocytes, and oligodendrocytes. Recent studies demonstrated that neural stem cells in the subventricular zone send extensions to the lateral ventricle and receive signals. Parkinson's disease, a neurodegenerative disorder, can be treated by supplying dopamine to improve symptoms, but this cannot be a curative treatment. Sooner or later, the dopaminergic neurons degenerate and become incapable of produce dopamine, resulting in deterioration of symptoms. Fetal nigral tissue transplantation can be one of the candidates of curative treatment, but is not regarded as a standard method due to ethical problems and difficulty in obtaining enough amount of such tissue. ES cells and iPS cells can be differentiated to dopaminergic cells, but the extent of differentiation and occasional occurrence of tumors must be controlled before applying to human. Immuno-rejectiv … More e reactions and ethical problems must be controlled. Degeneration of neurons in the nigrostriatal tract deplete striatal dopamine and causes Parkinson's disease. Striatum is located close to the lateral ventricle, suggesting that the subventricular neural stem cells are the good candidates for the treatment of this disease by causing proliferation, migration and differentiation. In the current project, we examined whether Eph/ephrin signaling system can be used to induce these phenomenon for the treatment of Parkinson's disease in rats and marmosettes. In rats, injection of clustered ephrin-A1 into the lateral ventricle could induce NSPC proliferation, migration and differentiation to dopaminergic neurons, and angiogenesis in the striatum. These effects resulted in behavioral improvement of rats with hemilateral nigrostriatal lesion. The histological and behavioral improvement lasted at least for 12 weeks. Marmosettes have so small a ventricle that it was difficult to inject clustered ephrin-A1 into the lateral ventricle. However, multiple injection of ephrin-A1 in and around the lateral ventricle improved the animal behavior as measured by Supermex. Recombinant ephrin-A1 fused with the coiled-coil domain of cartilage oligomeric matrix protein was produced in E. coli, but the product was not soluble and precipitated in water, probably due to formation of large multimers. Because of these results, we used the authentic method of clustering ephrin-A1-Fc by anti-IgG(Fc) antibody. Less