Modulation of adult stem cell fate by inhibitors of histone deacetylases

Epigenetic modulation of the chromatin structure influences cellular differentiation. Inhibitors of histone deacetylases (HDAC) are challenging compounds and increase chromatin hyperacetylation, which is associated with transcriptional activation. Among the panel of upregulated genes are neuronal transcription factors, which opens the intriguing possibility to target the fate of adult stem cell differentiation by HDAC inhibitors. Here, we tested whether HDAC inhibitors influence the differentiation pattern of adult stem cells obtained from rat subventricular zone. Valproic acid, sodium butyrate and MS-275, compounds with restricted HDAC inhibiting activity, as well as the highly efficient second generation HDAC inhibitors suberoylanilide hydroxamic acid and M344 were applied in neurosphere forming stem cell assays. All tested compounds were able to shift cell differentiation towards neuronal phenotypes. Double-immunofluorescent microscopy identified a highly significant increase of neurons in the range of 12–16% compared to untreated controls. Induction of neuronal differentiation was concentration-dependent, but independent of cultured cell densities. To unravel the molecular targets of HDAC inhibitors will be a challenging approach and helpful to further target neuronal differentiation from adult precursor cells in vitro.