Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells

Abstract

It has become apparent that chromatin modification plays a critical role in the regulation of cell-type-specific gene expression. Here, we show that an inhibitor of histone deacetylase, valproic acid (VPA), induced neuronal differentiation of adult hippocampal neural progenitors. In addition, VPA inhibited astrocyte and oligodendrocyte differentiation, even in conditions that favored lineagespecific differentiation. Among the VPA-up-regulated, neuronspecific genes, a neurogenic basic helix-loop-helix transcription factor, NeuroD, was identified. Overexpression of NeuroD resulted in the induction and suppression of neuronal and glial differentiation, respectively. These results suggest that VPA promotes neuronal fate and inhibits glial fate simultaneously through the induction of neurogenic transcription factors including NeuroD.cell fate specification ͉ chromatin ͉ neural stem cell ͉ valproic acid

In vitro differentiation of hepatic progenitor cells from mouse embryonic stem cells induced by sodium butyrate

“…Much is known about the mechanism of HDAC inhibitors effect on the transformed cells, however, little is known about the functional mechanism that exerts antiproliferative, induction of differentiation or apoptotic effects on the normal cells. Recently, HDAC inhibitors have been reported to inhibit cardiomyocyte differentiation of embryonic stem cells [Na et al, 2003], myofibroblastic differentiation of rat hepatic stellate cells [Niki et al, 1999], mediated neuronal differentiation of multi-potent adult neural progenitor cells [Hsieh et al, 2004], induction of osteogenic differentiation of human mesenchymal stem cells [Cho et al, 2005], and enhances the cytokine-induced expansion of human hematopoietic stem cells [De Felice et al, 2005]. According to our data, the differentiation system with the treatment of sodium butyrate allows ES cells differentiation into hepatic progenitor cells, moreover, VPA, another reported type II HDAC inhibitors, had similar effects on the process of differentiation (data not shown).…”

“…In addition, the majority of the treated cells remained in cell cycle for 3 days after the addition of sodium butyrate, but the cycling fraction decreased to 17% 7 days later [Rambhatla et al, 2003]. It was now established that treatment of cells both in vitro and in vivo with sodium butyrate, a potential histone deacetylase (HDAC) inhibitor, could result in specific functional outcomes such as proliferation, cell cycle arrest, apoptosis, or differentiation [Janson et al, 1997;Sambucetti et al, 1999;Wang et al, 1999;Travers et al, 2002;Camphausen et al, 2004;Hsieh et al, 2004;Bug et al, 2005;Cho et al, 2005;Jiang et al, 2005;Rossig et al, 2005]. Therefore it was assumed that the treatment with sodium butyrate would lead to the cell cycle arrest of the ES cells, and the removal of sodium butyrate might be important for the treated cells to reenter into cell cycle and consequently the cells with the capacity to proliferate and express hepatic linage markers could be acquired.…”

Effects of mood stabilizers on adult dentate gyrus-derived neural precursor cells

“…Moreover, recent reports have described that Li and VPA affect neurogenesis through increasing cell proliferation and/or promotion of neuronal differentiation of neural precursor cells (Chen et al, 2000;Son et al, 2003;Hao et al, 2004;Hsieh et al, 2004;Kim JS et al, 2004;Laeng et al, 2004;Wexler et al, 2008) and that Li blocks the effects of stress on depression-like behaviors through increasing hippocampal neurogenesis in adult rodent models (Silva et al, 2008). Results of these studies suggest that adult hippocampal neurogenesis plays an important role in the therapeutic action of mood stabilizers as well.…”

Epigenetic regulation of aging stem cells

“…Class I and II HDACs regulate adult stem and progenitor differentiation in both the adult hippocampus (Hsieh et al, 2004) and the postnatal SVZ (Siebzehnrubl et al, 2007). In hippocampal neural progenitors isolated from adult rats, global levels of histone acetylation on histone H3 and H4 decrease over the course of differentiation, with higher levels in neurons as opposed to astrocytes or oligodendrocytes (Hsieh et al, 2004). Pharmacological inhibition of class I and II HDACs by valproic acid in vivo and in culture decreases proliferation of adult hippocampal NSCs, while promoting differentiation to a neuronal fate (Hsieh et al, 2004).…”

“…In hippocampal neural progenitors isolated from adult rats, global levels of histone acetylation on histone H3 and H4 decrease over the course of differentiation, with higher levels in neurons as opposed to astrocytes or oligodendrocytes (Hsieh et al, 2004). Pharmacological inhibition of class I and II HDACs by valproic acid in vivo and in culture decreases proliferation of adult hippocampal NSCs, while promoting differentiation to a neuronal fate (Hsieh et al, 2004). The role of specific HDACs is currently under investigation.…”