In vitro generation and transplantation of precursor-derived human dopamine neurons

Abstract

The use of in vitro expanded human CNS precursors has the potential to overcome some of the ethical, logistic and technical problems of fetal tissue transplantation in Parkinson disease. Cultured rat mesencephalic precursors proliferate in response to bFGF and upon mitogen withdrawal, differentiate into functional dopamine neurons that alleviate motor symptoms in Parkinsonian rats (Studer et al. [1998] Nat. Neurosci. 1:290-295). The successful clinical application of CNS precursor technology in Parkinson disease will depend on the efficient in vitro generation of human dopaminergic neurons. We demonstrate that human dopamine neurons can be generated from both midbrain and cortical precursors. Transplantation of midbrain precursor-derived dopamine neurons into Parkinsonian rats resulted in grafts rich in tyrosine hydroxylase positive neurons 6 weeks after transplantation. No surviving tyrosine hydroxylase positive neurons could be detected when dopamine neurons derived from cortical precursors were grafted. Our data demonstrate in vitro derivation of human dopamine neurons from expanded CNS precursors and encourage further studies that systematically address in vivo function and clinical potential.