Keeping Them Quiet: BMPs Maintain Adult Neural Stem Cell Quiescence

Johnston, Mantissa A; Lim, Daniel A.

doi:10.1016/j.stem.2010.06.006

Cited by 7 publications

(7 citation statements)

References 10 publications

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“…Many developmental cues have been shown to operate in the adult NSC niche including Wnt [1], sonic hedgehog [2,3], bone morphogenic protein [4] and notch signaling [5,6]. More recently the modification of histone proteins has been identified as an epigenetic regulator of adult neurogenesis [7-9].…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells

et al. 2011

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BackgroundHistone deacetylases (HDACs) are enzymes that modulate gene expression and cellular processes by deacetylating histones and non-histone proteins. While small molecule inhibitors of HDAC activity (HDACi) are used clinically in the treatment of cancer, pre-clinical treatment models suggest they also exert neuroprotective effects and stimulate neurogenesis in neuropathological conditions. However, the direct effects of HDACi on cell cycle progression and proliferation, two properties required for continued neurogenesis, have not been fully characterized in adult neural stem cells (NSCs). In this study, we examined the effects of two broad class I and class II HDACi on adult mouse NSCs, the hydroxamate-based HDACi suberoylanilide hydroxamic acid (vorinostat, SAHA) and the short chain fatty acid HDACi sodium butyrate.ResultsWe show that both HDACi suppress the formation of neurospheres by adult mouse NSCs grown in proliferation culture conditions in vitro. DNA synthesis is significantly inhibited in adult mouse NSCs exposed to either SAHA or sodium butyrate and inhibition is associated with an arrest in the G1 phase of the cell cycle. HDACi exposure also resulted in transcriptional changes in adult mouse NSCs. Cdk inhibitor genes p21 and p27 transcript levels are increased and associated with elevated H3K9 acetylation levels at proximal promoter regions of p21 and p27. mRNA levels for notch effector Hes genes and Spry-box stem cell transcription factors are downregulated, whereas pro-neural transcription factors Neurog1 and Neurod1 are upregulated. Lastly, we show HDAC inhibition under proliferation culture conditions leads to long-term changes in cell fate in adult mouse NSCs induced to differentiate in vitro.ConclusionSAHA and sodium butyrate directly regulate cdk inhibitor transcription to control cell cycle progression in adult mouse NSCs. HDAC inhibition results in G1 arrest in adult mouse NSCs and transcriptional changes associated with activation of neuronal lineage commitment programs and a reduction of stem/progenitor state. Changes in differentiated cell state in adult mouse NSCs treated with HDACi under proliferation culture conditions suggests an intrinsic relationship between multipotency, cell cycle progression and HDAC activity in these cells.

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Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells

et al. 2011

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“…Studies have also been conducted to characterize the isolated cell population, using an anti-CD133 antibody as a specific cell surface marker to isolate CSCs (42). However, the antibodies routinely used as cell surface markers for CD133 target poorly specific glycoprotein epitopes, and skeptical arguments exist in using CD133 as a cell surface marker for CSCs (26). Recently, studies have been focusing on the functional analysis of CD133 itself.…”

Section: Discussionmentioning

confidence: 99%

“…Bone morphogenetic protein 4 (BMP4) is one of the most important factors in cell dynamics. BMP is a member of the transforming growth factor beta (TGF-β) family and plays a very important role in regulating cell proliferation, differentiation, and development in various biological systems (23)(24)(25)(26)(27). Interestingly, evidences that BMP4 can promote differentiation of GBM cells have been increasing (28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

BMP4 induces asymmetric cell division in human glioma stem-like cells

et al. 2019

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Glioblastoma (GBM) is a malignant tumor with a high recurrence rate and has very poor prognosis in humans. The median survival is still <2 years. Therefore, a new treatment strategy should be established. Recently, this cancer has been thought to be heterogeneous, consisting of cancer stem cells (CSCs) that are self-renewable, multipotent, and treatment resistant. So various strategies targeting glioma stem-like cells (GSCs) have been investigated. This study focused on strategies targeting GSCs through the induction of differentiation using bone morphogenetic protein 4 (BMP4). The expression of CD133, a cancer stem cell marker, under BMP4 treatment in GSCs was examined using flow cytometry, western blotting, and quantitative PCR. Immunofluorescent staining of GSCs was also performed to examine the type of cell division: asymmetric cell division (ACD) or symmetric cell division (SCD). We obtained the following results. The BMP4 treatment caused downregulation of CD133 expression. Moreover, it induced ACD in GSCs. While the ACD ratio was 23% without BMP4 treatment, it was 38% with BMP4 treatment (P=0.004). Furthermore, the tumor sphere assay demonstrated that BMP4 suppresses self-renewal ability. In conclusion, these findings may provide a new perspective on how BMP4 treatment reduces the tumorigenicity of GSCs.

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“…In these regions, the NSCs divide infrequently, and are characterized as quiescent. Bone morphogenetic protein (BMP) signalling affects adult NSC proliferation and cellular differentiation (Bonaguidi et al, 2008), and has recently been shown to play a role in regulating quiescence (Johnston & Lim, 2010).…”

Section: Neural Stem Cellsmentioning

confidence: 99%

A Mathematical Model of Noggin and BMP Densities in Adult Neural Stem Cells

Larripa

Gallegos

2017

LiB

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New neurons are generated in the adult hippocampus throughout life by neural stem cells (NSCs) in a dynamic process responsive to external signalling cues. NSCs in the adult hippocampus divide infrequently, and it has been shown that bone morphogenetic protein (BMP) modulates their quiescence. Infusion of Noggin, a BMP antagonist, blocks this signalling. We investigate the balance of BMP and Noggin in this particular niche and qualitatively reproduce experimental results obtained and qualitatively reproduce experimental results with a one-dimensional reaction-diffusion model. We use the model to connect BMP signalling profiles with specific cellular outcomes and to determine whether the transient infusion of BMP leads to a signalling profile which can be reversed by the infusion of Noggin. Additionally, we analyse the role of diffusion in this system for generating signalling profiles with dramatically different cell-fate outcomes and show that diffusion-driven instability is not possible in our system of reactiondiffusion equations.

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Keeping Them Quiet: BMPs Maintain Adult Neural Stem Cell Quiescence

Cited by 7 publications

References 10 publications

Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells

Histone deacetylase inhibitors SAHA and sodium butyrate block G1-to-S cell cycle progression in neurosphere formation by adult subventricular cells

BMP4 induces asymmetric cell division in human glioma stem-like cells

A Mathematical Model of Noggin and BMP Densities in Adult Neural Stem Cells

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