Human neural stem cells, brain transplantation and by uij90909


									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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