Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease
Article first published online: 10 APR 2006
Volume 26, Issue 2, pages 129–140, April 2006
How to Cite
Kim, S. U., Park, I. H., Kim, T. H., Kim, K. S., Choi, H. B., Hong, S. H., Bang, J. H., Lee, M. A., Joo, I. S., Lee, C. S. and Kim, Y. S. (2006), Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease. Neuropathology, 26: 129–140. doi: 10.1111/j.1440-1789.2006.00688.x
- Issue published online: 10 APR 2006
- Article first published online: 10 APR 2006
- Received 24 October 2005; accepted 1 November 2005.
- brain transplantation;
- cell therapy;
- GTP cyclohydrolase 1;
- HB1.F3 cell line;
- neural stem cells;
- Parkinson disease;
- tyrosine hydroxylase
Parkinson disease is a neurodegenerative disease characterized by loss of midbrain dopaminergic neurons resulting in movement disorder. Neural stem cells (NSC) of the CNS have recently aroused a great deal of interest, not only because of their importance in basic research of neural development, but also for their therapeutic potential in neurological disorders. We have recently generated an immortalized human NSC cell line, HB1.F3, via retrovirus-mediated v-myc transfer. This line is capable of self-renewal, is multipotent, and expresses cell specific markers for NSC, ATP-binding cassettes transporter (ABCG2) and nestin. Next, we co-transduced the F3 NSC line with genes encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GTPCH1) in order to generate dopamine-producing NSC. The F3.TH.GTPCH human NSC line expresses TH and GTPCH phenotypes as determined by RT-PCR, western blotting and immunocytochemistry, and shows a 800 to 2000-fold increase in production of l-dihydroxyphenyl alanine in HPLC analysis. A marked improvement in amphetamine-induced turning behavior was observed in parkinsonian rats implanted with F3.TH.GTPCH cells, but not in control rats receiving F3 NSC. In the animals showing functional improvement, a large number of TH-positive F3.TH.GTPCH NSC were found at injection sites. These results indicate that human NSC, genetically transduced with TH and GTPCH1 genes, have great potential in clinical utility for cell replacement therapy in patients suffering from Parkinson disease.