Environmental cue-dependent dopaminergic neuronal differentiation and functional effect of grafted neuroepithelial stem cells in Parkinsonian brain

OBJECTIVE: To physiologically repair damaged neural circuitry using neural transplantation, the donor cells must be able to differentiate into the optimal type and number of neurons for the host brain environment. They must also be capable of functional regulation by the host brain. These features are important to optimize functional outcome and to minimize side effects. In this study, the differentiation of grafted mesencephalic neuroepithelial stem cells in the normal and parkinsonian brain was assessed morphologically and behaviorally to confirm the influence of the host brain environment after neural transplantation regarding functional outcome and side effects of transplants. METHODS: Green fluorescent protein-positive mesencephalic neuroepithelial stem cells were dissected from early rat embryos and transplanted into normal (n = 20) and Parkinson's disease (PD) rat model striata (n = 30). The differentiation pattern of grafted cells was precisely monitored immunohistochemically, and the functional effects of grafted cells on behavior were assessed using an amphetamine-induced rotation test. RESULTS: The grafted cells survived in both normal and PD rat striata and differentiated into tyrosine hydroxylase-positive cells. In 8-week-old grafts, the number of tyrosine hydroxylase-positive cells was 3-fold higher in parkinsonian brains than in normal brains. The donor-derived tyrosine hydroxylase-positive cells exhibited a mature morphology with long, well-branched cell processes and large cell bodies, especially in parkinsonian brains. Also, the process lengths of these cells in parkinsonian brains were 3.4-fold longer than those in normal brains at 8 weeks after transplantation. The grafted PD rats exhibited a complete recovery from their behavioral defects, and no obvious contralateral rotation to the lesioned and grafted side suggestive of overdose supply from the graft was observed. However, the grafted normal rats did not exhibit any contralateral rotation to the grafted side suggestive of dopamine unbalance. CONCLUSION: Grafted mesencephalic neuroepithelial stem cells can differentiate into optimal neuron types in response to environmental cues and can affect the behavior of PD rats without any side effects.