A Combination of NT-4/5 and GDNF Is Favorable for Cultured Human Nigral Neural Progenitor Cells

Idiopathic Parkinson’s disease is a progressive neurodegenerative disorder clinically manifested by cardinal motor symptoms including tremor at rest, bradykinesia and muscle rigidity. Transplantation of dopaminergic neurons is an experimental therapy for Parkinson’s disease, however, limited by suboptimal integration and low survival of grafts. Pretreatment of donor tissue may offer a strategy to improve properties of transplanted dopaminergic neurons and thereby clinical outcome. We have previously shown that a combination of neurotrophin-4/5 (NT-4/5) and glial cell linederived neurotrophic factor (GDNF) demonstrated additive effects on rat ventral mesencephalic tissue. The present study investigated the effects of NT-4/5 and GDNF as single factors or in combination on dopaminergic neurons in organotypic explant cultures of fetal human ventral mesencephalon. For that purpose free-floating roller-tube cultures were prepared from ventral mesencephali and the equally sized pieces grown for one week in presence or absence of neurotrophic factors. Both neurotrophic factors increased dopamine content in the culture medium and number of tyrosine hydroxylase immunoreactive (ir) neurons, most prominently after combined GDNF+NT-4/5 treatment. Culture volumes did not differ between groups, while content of lactate dehydrogenase in the culture medium was moderately reduced in all treated groups. In conclusion, we identified that a combination of GDNF and NT-4/5 robustly promoted differentiation and survival of human fetal ventral mesencephalic dopaminergic neurons, an observation with potential promising impact for cell replacement approaches in Parkinson's disease.