Abstract
BackgroundEmerging studies of human pluripotent stem cells (hPSCs) raise new prospects for neurodegenerative disease modeling and cell replacement therapies. Therefore, understanding the mechanisms underlying the commitment of neural progenitor cells (NPCs) is important for the application of hPSCs in neurodegenerative disease therapies. It has been reported that epigenetic modifications of histones play important roles in neural differentiation, but the exact mechanisms in regulating hPSC differentiation towards NPCs are not fully elucidated.ResultsWe demonstrated that suppression of histone deacetylases (HDACs) promoted the differentiation of hPSCs towards NPCs. Application of HDAC inhibitors (HDACi) increased the expression of neuroectodermal markers and enhanced the neuroectodermal specification once neural differentiation was initiated, thereby leading to more NPC generation. Similarly, the transcriptome analysis showed that HDACi increased the expression levels of ectodermal markers and triggered the NPC differentiation related pathways, while decreasing the expression levels of endodermal and mesodermal markers. Furthermore, we documented that HDAC3 but not HDAC1 or HDAC2 was the critical regulator participating in NPC differentiation, and knockdown of HDAC3′s cofactor SMRT exhibited a similar effect as HDAC3 on NPC generation.ConclusionsOur study reveals that HDACs, especially HDAC3, negatively regulate the differentiation of hPSCs towards NPCs at an earlier stage of neural differentiation. Moreover, HDAC3 might function by forming a repressor complex with its cofactor SMRT during this process. Thus, our findings uncover an important epigenetic mechanism of HDAC3 in the differentiation of hPSCs towards NPCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-014-0095-z) contains supplementary material, which is available to authorized users.
Highlights
Emerging studies of human pluripotent stem cells raise new prospects for neurodegenerative disease modeling and cell replacement therapies
Nearly 95% of cells derived from neurospheres were NESTIN and SOX2 dual positive neural progenitor cells (NPCs) at the end of this stage (Figure 1B), suggesting that the cells which contributed to NPC generation survived during the neurosphere formation
Our results showed that transcripts of class I and class II histone deacetylases (HDACs) were increased once the differentiation was initiated and were kept at high levels in all stages, indicating that HDACs participate in the process of neural differentiation
Summary
Emerging studies of human pluripotent stem cells (hPSCs) raise new prospects for neurodegenerative disease modeling and cell replacement therapies. Understanding the mechanisms underlying the commitment of neural progenitor cells (NPCs) is important for the application of hPSCs in neurodegenerative disease therapies. Human pluripotent stem cells (hPSCs) including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) possess the potential to differentiate into all cell types of three germ layers, which raises new prospects for disease modeling, molecular mechanism finding and cell-replacement therapies of neurodegenerative diseases that have a very complex nature of pathogenesis. Blocking the BMP/SMAD signaling pathway with small molecules up-regulates the expression of neural transcription factors, such as SOX2, PAX6 and NESTIN, and, facilitates NPC generation from hPSCs [13]. FGF2 can antagonize BMP signaling to stabilize neural identity during early neural specification [14]
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