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Cell replacement and gene therapy using neural stem cells (NSCs) have beenwidely touted as a promising treatment for CNS diseases including brain tumors.Histone deacetylase (HDAC) inhibitors have been used to explore mechanisms behindthe lineage-specific differentiation of NSCs and as modulators of gene therapy.We have used the human embryonic midbrain stem cell line NGC-407 and the HDACinhibitor 4-phenylbutyrate (4-PB) to investigate the differentiation from epigeneticperspectives. NGC-407 cells can differentiate into both neurons and glial cells,evidenced by morphological characteristics as well as up-regulation of the respectivemarkers β-tubulin III and glial fibrillary acidic protein (GFAP) and simultaneousdown-regulation of the NSC-marker nestin. Genomic DNA extracted from the differentiatingcells was globally more methylated than that of the proliferating cells. The differentiatingcells showed increased expression of the de novo DNA methyltransferase DNMT3Balong with strong immunoreactivity in the cell nuclei. When these cells were treatedwith 4-PB, both the astrocytic and the neuronal differentiation phenotypes weresuppressed, which paralleled a substantially weakened DNMT3B immunoreactivityin the cell nuclei. Importantly, 4-PB treatment preserves the immature phenotypeof these differentiating cells as indicated by Western blot analysis and immunocytochemicalanalyses of the NSC markers, nestin and CD133. Nestin becomes entirely degraded5 days after induction of differentiation, but upon exposure to 4-PB, some ofthe differentiating cells retain the integrity of nestin and concurrently, CD133is also up-regulated. Taken together, the data suggests that HDAC activity isnecessary for human embryonic NSC differentiation.

international journal of molecular medicine

HDAC inhibitor 4-phenylbutyrate preserves immature phenotype of human embryonic midbrain stem cells: Implications for the involvement of DNA methyltransferase