scholarly journals UTX/KDM6A suppresses AP-1 and a gliogenesis program during neural differentiation of human pluripotent stem cells

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Beisi Xu ◽  
Brett Mulvey ◽  
Muneeb Salie ◽  
Xiaoyang Yang ◽  
Yurika Matsui ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Regulation ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Gene Activation ◽  
Histone H3 ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Human Neural Stem Cells

Abstract Background UTX/KDM6A is known to interact and influence multiple different chromatin modifiers to promote an open chromatin environment to facilitate gene activation, but its molecular activities in developmental gene regulation remain unclear. Results We report that in human neural stem cells, UTX binding correlates with both promotion and suppression of gene expression. These activities enable UTX to modulate neural stem cell self-renewal, promote neurogenesis, and suppress gliogenesis. In neural stem cells, UTX has a less influence over histone H3 lysine 27 and lysine 4 methylation but more predominantly affects histone H3 lysine 27 acetylation and chromatin accessibility. Furthermore, UTX suppresses components of AP-1 and, in turn, a gliogenesis program. Conclusions Our findings revealed that UTX coordinates dualistic gene regulation to govern neural stem cell properties and neurogenesis–gliogenesis switch.

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

Electroconductive nanoscale topography for enhanced neuronal differentiation and electrophysiological maturation of human neural stem cells

Nanoscale ◽  
2017 ◽  
Vol 9 (47) ◽  
pp. 18737-18752 ◽  
Author(s):  
Kisuk Yang ◽  
Seung Jung Yu ◽  
Jong Seung Lee ◽  
Hak-Rae Lee ◽  
Gyeong-Eon Chang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neuronal Differentiation ◽  
Neural Stem Cell ◽  
Human Neural Stem Cells ◽  
Nanoscale Topography

Electroconductive nanotopography for enhanced neurogenesis of neural stem cell.

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.

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 Stem Cell Bioprinting: Functional 3D Neural Mini-Tissues from Printed Gel-Based Bioink and Human Neural Stem Cells (Adv. Healthcare Mater. 12/2016)

2016 ◽  
Vol 5 (12) ◽  
pp. 1428-1428 ◽  
Author(s):  
Qi Gu ◽  
Eva Tomaskovic-Crook ◽  
Rodrigo Lozano ◽  
Yu Chen ◽  
Robert M. Kapsa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Human Neural Stem Cells

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 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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