Hypoxia suppresses neuronal functions in primary neuron, speeds cell cycle progression and affection the differentiation potential of neural stem cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE24131 | GEO | 2011/12/31
SECONDARY ACCESSION(S): PRJNA130125
REPOSITORIES: GEO
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Project description:Multiple diseases are associated with a pathological hypoxia in the brain, resulting in various neurological sequalae. Understanding the response to hypoxia of neurons and neural stem cells (NSCs) will help devise better therapeutic strategies. We have exposed primary neurons (PN) and neural stem cells to 1% O2. Both cell types survived well, and neurons showed no obvious morphological changes. The NSCs, however, became fusiform, and displayed a population of cells with accelerated transition in cell cycle. Gene expression profile through microarray analysis revealed major differences in response to hypoxia between NSC and PN. Not only the number of genes significantly changes was ~five-fold higher in NSC, but the types of genes involved and the direction of change was quite different. In particular, NSCs up-regulated multiple growth factors and down-regulated most other cytokines and metalloproteases , while PN down-regulated most neuronal-specific genes, up-regulated growth factors, with no major effect on cytokines. We conclude that hypoxia 1- accelerates cell cycle transition of NSC in a post-transcriptional fashion ; 2-affects cytokines in NSC but not in neurons; 3-result in up-regulation of multiple growth factors in NSC and PN; and 4-suppresses neuronal specific functions. 1) Primary neurons (PN) and neural stem cells were exposed to 1% O2. 2) Gene expression profile through microarray analysis was used to determine the differences in response to hypoxia between NSC and PN.
2011-12-31 | E-GEOD-24131 | biostudies-arrayexpress
Project description:Stem cells are a potential key strategy for treating neurodegenerative diseases in which the generation of new neurons is critical. A better understanding of the characteristics and molecular properties of neural stem cells (NSC) and differentiated neurons can help in assessing neuronal maturity and possibly in devising better therapeutic strategies. We have therefore performed an in-depth gene expression profiling study of the C17.2 NSC line and primary neurons (PN) derived from embryonic mouse brains. Microarray analysis revealed a neuron-specific gene expression signature that distinguishes PN from NSCs, with elevated levels of transcripts involved in neuronal functions such as neurite development, axon guidance, in PN. The same comparison revealed decreased levels of multiple cytokine transcripts such as IFN, TNF, TGF, and IL. Among the differentially expressed genes, we found a statistically significant enrichment of genes in the ephrin, neurotrophin, CDK5 and actin pathways which control multiple neuronal-specific functions. Furthermore, genes involved in cell cycle were among the most significantly changed in PN. In order to better understand the role of cell cycle arrest in mediating NSCs differentiation, we blocked the cell cycle of NSCs with Mitomycin C (MMC) and examined cellular morphology and gene expression signatures. Although these MMC-treated NSCs displayed a neuronal morphology and expressed some neuronal differentiation marker genes, their gene expression patterns was very different from primary neurons. We conclude that: 1) Fully differentiated primary neurons display a specific neuronal gene expression signature; 2) cell-cycle block in NSC does not induce the formation of fully differentiated neurons; 3) Cytokines such as IFN, TNF, TGF and IL are part of normal NSC function and/or physiology; 4) Signaling pathways of ephrin, neurotrophin, CDK5 and actin, related to major neuronal features, are dynamically enriched in genes showing changes in expression level. Gene expression profiles in neuronal stem cell, mitomycin-treated neuronal stem cells and primary neuronal cultures were compared to examine cellular morphology and gene expression signatures during neuronal differentiation.
2011-11-28 | E-GEOD-24116 | biostudies-arrayexpress
Project description:Stem cells are a potential key strategy for treating neurodegenerative diseases in which the generation of new neurons is critical. A better understanding of the characteristics and molecular properties of neural stem cells (NSC) and differentiated neurons can help in assessing neuronal maturity and possibly in devising better therapeutic strategies. We have therefore performed an in-depth gene expression profiling study of the C17.2 NSC line and primary neurons (PN) derived from embryonic mouse brains. Microarray analysis revealed a neuron-specific gene expression signature that distinguishes PN from NSCs, with elevated levels of transcripts involved in neuronal functions such as neurite development, axon guidance, in PN. The same comparison revealed decreased levels of multiple cytokine transcripts such as IFN, TNF, TGF, and IL. Among the differentially expressed genes, we found a statistically significant enrichment of genes in the ephrin, neurotrophin, CDK5 and actin pathways which control multiple neuronal-specific functions. Furthermore, genes involved in cell cycle were among the most significantly changed in PN. In order to better understand the role of cell cycle arrest in mediating NSCs differentiation, we blocked the cell cycle of NSCs with Mitomycin C (MMC) and examined cellular morphology and gene expression signatures. Although these MMC-treated NSCs displayed a neuronal morphology and expressed some neuronal differentiation marker genes, their gene expression patterns was very different from primary neurons. We conclude that: 1) Fully differentiated primary neurons display a specific neuronal gene expression signature; 2) cell-cycle block in NSC does not induce the formation of fully differentiated neurons; 3) Cytokines such as IFN, TNF, TGF and IL are part of normal NSC function and/or physiology; 4) Signaling pathways of ephrin, neurotrophin, CDK5 and actin, related to major neuronal features, are dynamically enriched in genes showing changes in expression level.
2011-11-28 | GSE24116 | GEO
Project description:Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to enhance stem cell function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term (ST-NSC) and long-term NSCs (LT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-NSCs are maintained for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC pro-aging factor. Treatment with the Abl-inhibitor Imatinib increased NSC proliferation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable to cellular aging, yet NSC function can be partially restored.
2021-03-03 | GSE168031 | GEO
Project description:In Alzheimer’s disease (AD), reduced neural stem cell (NSC) plasticity causes reduced neurogenesis. Therefore, supplying the brain with new neurons using endogenous neurogenic reservoir – NSCs - might counteract the progression of AD. However, the mechanisms that enhance NSC plasticity are unknown. We recently generated an AD model in adult zebrafish brain where NSCs could react by enhanced plasticity and neurogenesis, and identified Interleukin-4 (IL4) as a key factor underlying this ability. Although IL4 directly regulated NSCs through its receptor IL4R, it was not clear how IL4R-negative NSCs would enhance their proliferation. Here, by performing whole tissue and single cell transcriptomics, we report that IL4 regulates IL4R-negative NSCs through modulating tryptophan metabolism by reducing the availability of Serotonin (5-HT) that suppresses NSC plasticity. 5-HT receptor htr1+ is only expressed in periventricular neurons where 5-HT balances the expression of brain-derived neurotrophic factor (bdnf), which promotes NSC proliferation through its receptor NGFRA, which is predominantly expressed in IL4R-negative NSCs. AD conditions induce IL4 that reduce 5-HT levels, and suppresses the suppressive effect on BDNF levels. Elevated levels of BDNF activate, through NGFRA, the proliferative output of the IL4R-negative NSCs. 5-HT overexpression dramatically reduces BDNF and proliferative ability of NSCs. Our results identify a novel IL4-dependent balancing mechanism on NSC proliferation by 5-HT through an intermediary regulatory cascade via HTR1, and BDNF/NGFRA signaling between periventricular neurons and NSCs. Our findings mark the heterogeneity of NSCs in response to direct or indirect regulation by IL4 – a biomarker for neurodegeneration-induced NSC plasticity.
2020-01-24 | GSE124162 | GEO
Project description:The neural stem cell (NSC) niche controls the expansion and differentiation of NSCs. Blood vessels are part of this neurogenic niche, but their functional significance for the regulation of NSC differentiation and the mechanisms involved remain unclear. Here, we report that blood vessel formation in the developing mouse and ferret cortex coincided with induction of NSC differentiation in time and space. Moreover, selective inhibition of brain angiogenesis in vessel-specific Gpr124 null embryos caused hypoxia and increased NSC expansion at the expense of differentiation. The hypoxia-inducible factor (HIF)-1Îą mediated this process, as the level of HIF-1Îą controlled NSC differentiation. Niche blood vessels regulated NSC differentiation at least in part by providing oxygen, as exposure to increased ambient oxygen levels rescued NSC differentiation in hypoxic brains of Gpr124 deficient embryos. Our findings establish a novel oxygen-dependent mechanism of how blood vessels regulate NSC differentiation.
2016-02-04 | E-MTAB-3941 | biostudies-arrayexpress
Project description:Neural stem cell (NSC) maintenance and functions are regulated by reactive oxygen species (ROS). However, the mechanisms by which ROS control NSC behavior remain unclear. Here we report that ROS-dependent Igfbp2 signaling controls DNA repair pathways which balance NSC self-renewal and lineage commitment. Ncf1 or Igfbp2 deficiency constrained NSCs to a self-renewing state and prevented neurosphere formation due to absent Igfbp2 cysteine-43 oxidation. Ncf1-dependent oxidation of Igfbp2 promoted neurogenesis by NSCs in vitro and in vivo, while repressing Brca1 DNA damage response genes and inducing DNA double-strand breaks (DDSBs). By contrast, Ncf1–/– and Igfbp2–/– NSCs favored the formation of oligodendrocytes in vitro and in vivo. Notably, transient repression of Brca1 DNA repair pathway genes induced DDSBs and was sufficient to rescue the ability of Ncf1–/– and Igfbp2–/– NSCs to lineage-commit to form neurospheres and neurons. Our study highlights the role of DNA damage/repair in orchestrating NSC fate decisions downstream of redox-regulated Igfbp2.
2023-01-17 | GSE221955 | GEO
Project description:A cardinal property of neural stem cells (NSCs) is their ability to adopt multiple fates upon differentiation. The epigenome is widely seen as a read-out of cellular potential and a manifestation of this can be seen in embryonic stem cells (ESCs), where promoters of many lineage-specific regulators are marked by a bivalent epigenetic signature comprising trimethylation of both lysine 4 and lysine 27 of histone H3 (H3K4me3 and H3K27me3, respectively). Bivalency has subsequently emerged as a powerful epigenetic indicator of stem cell potential. Here, we have interrogated the epigenome during differentiation of ESC-derived NSCs to immature GABAergic interneurons. We show that developmental transitions are accompanied by loss of bivalency at many promoters in line with their increasing developmental restriction from pluripotent ESC through multipotent NSC to committed GABAergic interneuron. At the NSC stage, the promoters of genes encoding many transcriptional regulators required for differentiation of multiple neuronal subtypes and neural crest appear to be bivalent, consistent with the broad developmental potential of NSCs. Upon differentiation to GABAergic neurons, all non-GABAergic promoters resolve to H3K27me3 monovalency, whereas GABAergic promoters resolve to H3K4me3 monovalency or retain bivalency. Importantly, many of these epigenetic changes occur prior to any corresponding changes in gene expression. Intriguingly, another group of gene promoters gain bivalency as NSCs differentiate toward neurons, the majority of which are associated with functions connected with maturation and establishment and maintenance of connectivity. These data show that bivalency provides a dynamic epigenetic signature of developmental potential in both NSCs and in early neurons. Neural stem cells derived from mouse embryonic stem cells were differentiated into neurons and FACS purified based on RedStar fluorescence driven by the Tau promoter. Chromatin was prepared from NSCs and neurons (n=1), sonicated to roughly 300bp and immunoprecipitated with antibodies against H3K4me3, H3K27me3, total Histone H3 and total IgG, alongside a 5% input sample. K4/K27 and corresponding input samples were analysed by ChIPSeq
2013-06-09 | E-GEOD-46792 | biostudies-arrayexpress
Project description:A cardinal property of neural stem cells (NSCs) is their ability to adopt multiple fates upon differentiation. The epigenome is widely seen as a read-out of cellular potential and a manifestation of this can be seen in embryonic stem cells (ESCs), where promoters of many lineage-specific regulators are marked by a bivalent epigenetic signature comprising trimethylation of both lysine 4 and lysine 27 of histone H3 (H3K4me3 and H3K27me3, respectively). Bivalency has subsequently emerged as a powerful epigenetic indicator of stem cell potential. Here, we have interrogated the epigenome during differentiation of ESC-derived NSCs to immature GABAergic interneurons. We show that developmental transitions are accompanied by loss of bivalency at many promoters in line with their increasing developmental restriction from pluripotent ESC through multipotent NSC to committed GABAergic interneuron. At the NSC stage, the promoters of genes encoding many transcriptional regulators required for differentiation of multiple neuronal subtypes and neural crest appear to be bivalent, consistent with the broad developmental potential of NSCs. Upon differentiation to GABAergic neurons, all non-GABAergic promoters resolve to H3K27me3 monovalency, whereas GABAergic promoters resolve to H3K4me3 monovalency or retain bivalency. Importantly, many of these epigenetic changes occur prior to any corresponding changes in gene expression. Intriguingly, another group of gene promoters gain bivalency as NSCs differentiate toward neurons, the majority of which are associated with functions connected with maturation and establishment and maintenance of connectivity. These data show that bivalency provides a dynamic epigenetic signature of developmental potential in both NSCs and in early neurons. Illumina Expresson BeadChip arrays (MouseRef-8v2.0) were used to assess gene expression changes in neural stem cells (n=5; derived from mouse embryonic stem cells) and their differentiated neuronal progeny (n=3; FACS-purified based on Tau-RedStar expression).
2013-06-09 | E-GEOD-46791 | biostudies-arrayexpress
Project description:Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
2020-02-19 | GSE137852 | GEO