Human neural stem cells, brain transplantation and regenerative medicine Seung U. Kim, MD, PhD Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea; Department of Neurology, University of British Columbia, Vancouver, Canada Cell replacement and gene transfer to the diseased or injured CNS have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. An ideal source of brain transplantation is human neural stem cells (NSCs) that could integrate into host brain tissue and differentiate into neurons or glial cells in response to environmental cues. We have recently generated stable, immortalized cell lines of NSCs from primary human fetal telencephalon via a retroviral vector encoding v-myc. HB1.F3, one of the NSC lines, expresses nestin, Musashi1 and ABCG2, cell type-specific markers for NSCs, carries normal human karyotype of 46XX. F3 NSCs have the ability to self- renew, and differentiate into cells of neuronal and glial lineage in vitro and in vivo. In rat cerebral hemorrhage (ICH) stroke model, transplanted human NSCs migrated selectively to the peri-hematomal areas and differentiated into neurons, and induced a marked behavioral improvement. For Parkinson disease (PD) studies, F3 NSCs were transduced to express human genes for tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GTPCH1), and transplanted into the striatum of rat PD model to replace missing dopaminergic neurons. There was a marked improvement in amphetamine-induced turning behavior in these animals and a good survival of TH+ NSCs in the host striatum. In neurotoxin-induced Huntington disease (HD) model, F3 NSCs were transduced with a human BDNF gene, and proactive human NSCs protected host striatal neurons from cell death caused by application of neurotoxin. In animals bearing brain tumor F3 NSCs show extensive migratory and tumor-tropic properties in vivo. Intracranial injection of human F3.CD cells carrying a suicide gene cytosine deaminase (CD) and application of fluorocytosine prodrug resulted in a significant anti-tumor response in rat glioblastoma models. The experimental results we have generated indicate that human NSC- based cell therapy has the great potential to prevent or restore anatomic or functional deficits associated with injury or disease in the CNS. (supported by KOSEF-BDRC Ajou University and Canadian Myelin Research Initiative).
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