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

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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