How Sox2 maintains neural stem cell identity

2013 ◽  
Vol 450 (3) ◽  
pp. e1-e2 ◽  
Author(s):  
Gerald Thiel
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Neural Development ◽  
Target Genes ◽  
Developmental Stages ◽  
Survivin Expression ◽  
Stem Cell Marker ◽  
Loss Of Function

The transcription factor Sox2 [SRY (sex-determining region Y)-box 2] is expressed at the earliest developmental stages in the nervous system and functions as a marker protein for neural development. Sox2 is found in embryonic neural stem cells as well as in virtually all adult neural stem cells of the subventricular region and the subgranular zone of the hippocampus. Gain-of-function and loss-of-function experiments in transgenic animals revealed a key role for Sox2 in the maintenance of neural stem cell properties, including proliferation/survival, self-renewal and neurogenesis. A limited set of Sox2-responsive target genes have been identified, including the genes encoding the neural stem cell marker nestin and the signalling molecule sonic hedgehog. In this issue of the Biochemical Journal, Feng et al. identified the survivin gene as a target for Sox2 in neural stem cells. Survivin protects cells from programmed cell death and functions as a regulator of cell division. The regulation of survivin expression by Sox2 explains why the reduction of the Sox2 concentration in neural stem cells is accompanied by a reduced proliferation of the cells and an induction of apoptosis. It would be of interest to know whether the Sox2–survivin connection is a common scheme to maintain the ‘stemness’ identity of other stem/progenitor cells.

scholarly journals Histone Demethylase LSD1 Regulates Neural Stem Cell Proliferation

2010 ◽  
Vol 30 (8) ◽  
pp. 1997-2005 ◽  
Author(s):  
GuoQiang Sun ◽  
Kamil Alzayady ◽  
Richard Stewart ◽  
Peng Ye ◽  
Su Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Target Genes ◽  
Neural Progenitor ◽  
Stem Cell Proliferation ◽  
Neural Stem Cell Proliferation ◽  
Cell Proliferation Inhibition

ABSTRACT Lysine-specific demethylase 1 (LSD1) functions as a transcriptional coregulator by modulating histone methylation. Its role in neural stem cells has not been studied. We show here for the first time that LSD1 serves as a key regulator of neural stem cell proliferation. Inhibition of LSD1 activity or knockdown of LSD1 expression led to dramatically reduced neural stem cell proliferation. LSD1 is recruited by nuclear receptor TLX, an essential neural stem cell regulator, to the promoters of TLX target genes to repress the expression of these genes, which are known regulators of cell proliferation. The importance of LSD1 function in neural stem cells was further supported by the observation that intracranial viral transduction of the LSD1 small interfering RNA (siRNA) or intraperitoneal injection of the LSD1 inhibitors pargyline and tranylcypromine led to dramatically reduced neural progenitor proliferation in the hippocampal dentate gyri of wild-type adult mouse brains. However, knockout of TLX expression abolished the inhibitory effect of pargyline and tranylcypromine on neural progenitor proliferation, suggesting that TLX is critical for the LSD1 inhibitor effect. These findings revealed a novel role for LSD1 in neural stem cell proliferation and uncovered a mechanism for neural stem cell proliferation through recruitment of LSD1 to modulate TLX activity.

scholarly journals Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α

2019 ◽  
Vol 116 (16) ◽  
pp. 8000-8009 ◽  
Author(s):  
Jose L. Nieto-González ◽  
Leonardo Gómez-Sánchez ◽  
Fabiola Mavillard ◽  
Pedro Linares-Clemente ◽  
María C. Rivero ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Molecular Mechanisms ◽  
Radial Glia ◽  
Brain Dysfunction ◽  
Mtor Signaling ◽  
Cysteine String Protein ◽  
Newborn Neurons

Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuit-independent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration.

scholarly journals Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2)

2020 ◽  
Vol 91 (4) ◽  
pp. 396-401 ◽  
Author(s):  
Keith W Muir ◽  
Diederik Bulters ◽  
Mark Willmot ◽  
Nikola Sprigg ◽  
Anand Dixit ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Multicentre Study ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Upper Limb ◽  
Limb Movement ◽  
Human Neural Stem Cells ◽  
Human Neural Stem Cell ◽  
Cell Implantation

BackgroundHuman neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute—chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study.MethodsWe undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2–13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation.FindingsTwenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures.InterpretationAdministration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials.FundingReNeuron, Innovate UK (application no 32074-222145).Trial registration numberEudraCT Number: 2012-003482-18

Multifunctional silica-coated iron oxide nanoparticles: a facile four-in-one system for in situ study of neural stem cell harvesting

2014 ◽  
Vol 175 ◽  
pp. 13-26 ◽  
Author(s):  
Yung-Kang Peng ◽  
Cathy N. P. Lui ◽  
Tsen-Hsuan Lin ◽  
Chen Chang ◽  
Pi-Tai Chou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Iron Oxide ◽  
Magnetic Resonance ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Cell Therapies ◽  
Bimodal Imaging

Neural stem cells (NSCs), which generate the main phenotypes of the nervous system, are multipotent cells and are able to differentiate into multiple cell types via external stimuli from the environment. The extraction, modification and re-application of NSCs have thus attracted much attention and raised hopes for novel neural stem cell therapies and regenerative medicine. However, few studies have successfully identified the distribution of NSCs in a live brain and monitored the corresponding extraction processes both in vitro and in vivo. To address those difficulties, in this study multi-functional uniform nanoparticles comprising an iron oxide core and a functionalized silica shell (Fe3O4@SiO2(FITC)-CD133, FITC: a green emissive dye, CD133: anti-CD133 antibody) have been strategically designed and synthesized for use as probe nanocomposites that provide four-in-one functionality, i.e., magnetic agitation, dual imaging (both magnetic resonance and optical) and specific targeting. It is shown that these newly synthesized Fe3O4@SiO2(FITC)-CD133 particles have clearly demonstrated their versatility in various applications. (1) The magnetic core enables magnetic cell collection and T2 magnetic resonance imaging. (2) The fluorescent FITC embedded in the silica framework enables optical imaging. (3) CD133 anchored on the outermost surface is demonstrated to be capable of targeting neural stem cells for cell collection and bimodal imaging.

scholarly journals The Impact of Cannabinoid Exposure on Glucocorticoid Receptor Signaling in Neural Stem Cells

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A73-A73
Author(s):  
Nikki Gill ◽  
Suban Burale ◽  
Neerupma Silswal ◽  
Donald Benedict DeFranco ◽  
Paula Monaghan-Nichols
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Preterm Birth ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Cannabis Use ◽  
Biological Impact ◽  
Proliferation And Differentiation ◽  
The Impact

Abstract Preterm birth-birth before 37 weeks of pregnancy-can cause many short- and long-term complications in newborns, including respiratory distress syndrome (RDS). RDS results from incomplete lung development and a surfactant deficiency, and it is a major factor of pre-term mortality. Synthetic glucocorticoids (sGCs) such as Betamethasone or Dexamethasone (Beta, Dex) are administered prenatally to women at risk of pre-term birth to prevent preterm complications. While sGCs are known to improve outcome, they also cause alterations in brain development and neural stem cell biology that are associated with long-term neurological defects. One common recreational drug used during pregnancy is cannabis. Some of the active components of cannabis include cannabinoids, which interact with the endocannabinoid receptor pathway in cells. Cannabinoids have been shown to induce proliferation and differentiation of embryonic neural stem cells (NSCs). We hypothesized that maternal cannabis use activates cannabinoid signaling pathways and leads to changes in glucocorticoid signaling in the developing brain. The purpose of this study was to determine whether cannabis use leads to a better or worse neurological outcome for children born pre-term and treated with sGCs for RDS. Neural stem cell neurospheres (NSCs) were isolated from the cerebral cortex of mice and treated with Vehicle (ethanol), Dex, cannabinoid receptor agonist WIN-55,212-2 (Win), or a combination WinDex. The transcriptional profile induced by exposure to Vehicle, Dex, and WinDex RNA were analyzed using microarray analyses examining the complete expressed genome. Gene Chip profiles indicated that both glucocorticoids and cannabinoids induce distinct transcriptional responses in E14.5 NSCs. The genes involved in proliferation-including S100a11, Jun, and Bex2-were repressed by Dex whereas WinDex rescued some of these expression profiles. Some genes encoding microRNA that inhibit our top target coding genes implicated in proliferation showed a greater induction by Dex compared to WinDex. Quantitative Polymerase Chain Reaction (qPCR) was performed to validate our genes of interest, including Adm, which has been shown to induce neural stem cell proliferation and differentiation. The biological impact of Winn on Dex-induced changes in NSC function were examined by in-vitro proliferation and differentiation studies using antibodies to Tuj1 (neurons), GFAP (glia), and CNPase (immature oligodendrocytes). The experiments indicate that Dex increased neuronal and oligodendrocyte differentiation, while WinDex appeared to reverse this phenotype in neurons. These studies suggest that cannabis use during pregnancy may limit the biological impact sGCs for preterm birth and lead to distinct cellular responses.

scholarly journals Momordica Charantia Polysaccharides Modulate the Differentiation of Neural Stem Cells via SIRT1/Β-Catenin Axis in Cerebral Ischemia/Reperfusion

2020 ◽  
Author(s):  
Zhaoli Hu ◽  
Fengying Li ◽  
Xiaoling Zhou ◽  
Feng Zhang ◽  
Linyan Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Reperfusion Injury ◽  
Neuronal Differentiation ◽  
Molecular Mechanism ◽  
Neural Stem Cell ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Neuroprotective Effects

Abstract Background Stroke is the leading cause of long-term motor disability and cognitive impairment. Recently, neurogenesis has become an attractive strategy for the chronic recovery of stroke. It is important to understand the molecular mechanism that promotes neural stem cell (NSC) neurogenesis for future NSC-based therapies. Our previous study showed that Momordica charantia polysaccharides (MCPs) exerted neuroprotective effects on stroke via their antioxidant and anti-inflammation activities. However, it remains unknown whether MCPs promote NSC neurogenesis after cerebral ischemic/reperfusion injury (IRI). Methods We investigated MCPs’ function in differentiation of NSCs in vitro experiments. Primary NSCs and neural stem cell line C17.2 were cultured and subjected to glutamate stimulation to establish the cell model of ischemia / reperfusion injury (IRI). We evaluated the effect of MCPs on NSC differentiation in IRI cell model by Western blot and immunofluorescence staining. The SIRT1 activity of NSCs post glutamate stimulation were also evaluated by CELL SIRT1 COLORIMETRY ASSAY KIT. In addition, molecular mechanism was clarified by employing the activator and inhibitor of SIRT1. Results MCPs had no effects on the differentiation of neural stem cells under physiological conditions, while shifted NSC differentiation potential from the gliogenic to neurogenic lineage under pathological conditions. Activation of SIRT1 with MCPs was responsible for the neuronal differentiation of C17.2-NSCs. The neuronal differentiation effect of MCPs was attributed to upregulation SIRT1-mediated deacetylation of β-catenin. MCPs-induced deacetylation via SIRT1 promoted nuclear accumulation of β-catenin in NSCs. Conclusion Our findings indicate that the deacetylation of β-catenin by SIRT1 represents a critical mechanism of action of MCPs in promoting NSC neuronal differentiation. It provides an improved understanding of molecular mechanism underlying neuroprotective effects of MCPs in IRI, indicating its potential role on treating ischemic stroke especially chronic recovery.

scholarly journals Instructive starPEG-Heparin biohybrid 3D cultures for modeling human neural stem cell plasticity, neurogenesis, and neurodegeneration

2017 ◽  
Author(s):  
Christos Papadimitriou ◽  
Mehmet I. Cosacak ◽  
Violeta Mashkaryan ◽  
Hilal Celikkaya ◽  
Laura Bray ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Development ◽  
Network Formation ◽  
Cell Plasticity ◽  
Stem Cell Plasticity ◽  
3D Cultures ◽  
Human Brains ◽  
Regenerative Therapies

AbstractThree-dimensional models of human neural development and neurodegeneration are crucial when exploring stem-cell-based regenerative therapies in a tissue-mimetic manner. However, existing 3D culture systems are not sufficient to model the inherent plasticity of NSCs due to their ill-defined composition and lack of controllability of the physical properties. Adapting a glycosaminoglycan-based, cell-responsive hydrogel platform, we stimulated primary and induced human neural stem cells (NSCs) to manifest neurogenic plasticity and form extensive neuronal networks in vitro. The 3D cultures exhibited neurotransmitter responsiveness, electrophysiological activity, and tissue-specific extracellular matrix (ECM) deposition. By whole transcriptome sequencing, we identified that 3D cultures express mature neuronal markers, and reflect the in vivo make-up of mature cortical neurons compared to 2D cultures. Thus, our data suggest that our established 3D hydrogel culture supports the tissue-mimetic maturation of human neurons. We also exemplarily modeled neurodegenerative conditions by treating the cultures with Aβ42 peptide and observed the known human pathological effects of Alzheimer’s disease including reduced NSC proliferation, impaired neuronal network formation, synaptic loss and failure in ECM deposition as well as elevated Tau hyperphosphorylation and formation of neurofibrillary tangles. We determined the changes in transcriptomes of primary and induced NSC-derived neurons after Aβ42, providing a useful resource for further studies. Thus, our hydrogel-based human cortical 3D cell culture is a powerful platform for studying various aspects of neural development and neurodegeneration, as exemplified for Aβ42 toxicity and neurogenic stem cell plasticity.SignificanceNeural stem cells (NSC) are reservoir for new neurons in human brains, yet they fail to form neurons after neurodegeneration. Therefore, understanding the potential use of NSCs for stem cell-based regenerative therapies requires tissue-mimetic humanized experimental systems. We report the adaptation of a 3D bio-instructive hydrogel culture system where human NSCs form neurons that later form networks in a controlled microenvironment. We also modeled neurodegenerative toxicity by using Amyloid-beta4 peptide, a hallmark of Alzheimer’s disease, observed phenotypes reminiscent of human brains, and determined the global gene expression changes during development and degeneration of neurons. Thus, our reductionist humanized culture model will be an important tool to address NSC plasticity, neurogenicity, and network formation in health and disease.

scholarly journals Fractone bulbs derive from ependymal cells and their laminin composition influence the stem cell niche in the subventricular zone

2016 ◽  
Author(s):  
Marcos Assis Nascimento ◽  
Lydia Sorokin ◽  
Tatiana Coelho-Sampaio
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Adult Neurogenesis ◽  
Subventricular Zone ◽  
Stem Cell Niche ◽  
Ependymal Cells ◽  
Cell Niche

AbstractFractones are extracellular matrix structures in the neural stem cell niche of the subventricular zone (SVZ), where they appear as round deposits named bulbs or thin branching lines called stems. Their cellular origin and what determines their localization at this site is poorly studied and it remains unclear whether they influence neural stem and progenitor cells formation, proliferation and/or maintenance. To address these questions, we analyzed whole mount preparations of the lateral ventricle by confocal microscopy using different extracellular matrix and cell markers. We found that bulbs are rarely connected to stems and that they contain laminin α5 and α2 chains, respectively. Fractone bulbs were profusely distributed throughout the SVZ and appeared associated with the center of pinwheels, a critical site for adult neurogenesis. We demonstrate that bulbs appear at the apical membrane of ependymal cells at the end of the first week after birth. The use of transgenic mice lacking laminin α5 gene expression (Lama5) in endothelium and in FoxJ1-expressing ependymal cells, revealed ependymal cells as the source of laminin α5-containing fractone bulbs. Loss of laminin α5 from bulbs correlated with a 60% increase in cell proliferation, as determined by PH3 staining, and with a selective reduction in the number of quiescent neural stem cells in the SVZ. These results indicate that fractones are a key component of the SVZ and suggest that laminin α5 modulates the physiology of the neural stem cell niche.Significance StatementOur work unveils key aspects of fractones, extracellular matrix structures present in the SVZ that still lack a comprehensive characterization. We show that fractones extensively interact with neural stem cells, whereas some of them are located precisely at pinwheel centers, which are hotspots for adult neurogenesis. Our results also demonstrate that fractones increase in size during aging and that their interactions with NSPCs become more complex in old mice. Lastly, we show that fractone bulbs are produced by ependymal cells and that their laminin content regulates neural stem cells.

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