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  1. Sonic Hedgehog Regulation of the Neural Precursor Cell Fate During Chicken Optic Tectum Development
    Yang C, Li X, Li Q, Li H, Qiao L, Guo Z, et al.
    J Mol Neurosci, 2018 Feb;64(2):287-299.
    PMID: 29285739 DOI: 10.1007/s12031-017-1019-5
    During nervous system development, neurons project axons over long distances to reach the appropriate targets for correct neural circuit formation. Sonic hedgehog (Shh) is a secreted protein and plays a key role in regulating vertebrate embryogenesis, especially in central nervous system (CNS) patterning, including neuronal migration and axonal projection in the brain and spinal cord. In the developing ventral midbrain, Shh is sufficient to specify a striped pattern of cell fates. Little is known about the molecular mechanisms underlying the Shh regulation of the neural precursor cell fate during the optic tectum development. Here, we aimed at studying how Shh might regulate chicken optic tectum patterning. In the present study, in ovo electroporation methods were employed to achieve the overexpression of Shh in the optic tectum during chicken embryo development. Besides, the study combined in ovo electroporation and neuron isolation culturing to study the function of Shh in vivo and in vitro. The fluorescent immunohistochemistry methods were used to check the related indicators. The results showed that Shh overexpression caused 87.8% of cells to be distributed to the stratum griseum central (SGC) layer, while only 39.3% of the GFP-transfected cells resided in the SGC layer in the control group. Shh overexpression also reduced the axon length in vivo and in vitro. In conclusion, we provide evidence that Shh regulates the neural precursor cell fate during chicken optic tectum development. Shh overexpression impairs neuronal migration and may affect the fate determination of transfected neurons.
    Matched MeSH terms: Neural Stem Cells/metabolism*
  2. Fulltext Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor
    Wei GZ, Martin KA, Xing PY, Agrawal R, Whiley L, Wood TK, et al.
    Proc Natl Acad Sci U S A, 2021 Jul 06;118(27).
    PMID: 34210797 DOI: 10.1073/pnas.2021091118
    While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR-/-) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
    Matched MeSH terms: Neural Stem Cells/metabolism
  3. Targeting glucose metabolism with dichloroacetate (DCA) reduces zika virus replication in brain cortical progenitors at different stages of maturation
    Gilbert-Jaramillo J, Komarasamy TV, Balasubramaniam VR, Heather LC, James WS
    Antiviral Res, 2024 Aug;228:105933.
    PMID: 38851593 DOI: 10.1016/j.antiviral.2024.105933
    The underlying threat of new Zika virus (ZIKV) outbreaks remains, as no vaccines or therapies have yet been developed. In vitro research has shown that glycolysis is a key factor to enable sustained ZIKV replication in neuroprogenitors. However, neither in vivo nor clinical investigation of glycolytic modulators as potential therapeutics for ZIKV-related fetal abnormalities has been conducted. Accordingly, we tested the therapeutic potential of metabolic modulators in relevant in vitro systems comprising two pools of neuroprogenitors (NPCs), which resemble early and late stages of pregnancy. Effective doses of metabolic modulators [3.0 μM] dimethyl fumarate (DMF), [3.2 mM] dichloroacetate (DCA), and [6.3 μM] VER-246608 were determined for these cells by their effect on lactate release, pyruvate dehydrogenase (PDH) activity and cell survival. The drugs were used in a 24h pre-treatment and kept throughout ZIKV infection of NPCs. Drug effects and ZIKV replication were assessed at 24- and 56-h post-infection. In early NPCs treated with DMF, DCA and VER-246608, there was a significant reduction in the extracellular release of ZIKV potentially by PDH-mediated increased mitochondrial oxidation of glucose. Out of the three drugs, only DCA was observed to reduce viral replication in late NPCs treated with DCA. Altogether, our findings suggest that reduction of anaerobic glycolysis could be of therapeutic potential against ZIKV-related fetal abnormalities and that clinical translation should consider the use of specific glycolytic modulators over different trimesters.
    Matched MeSH terms: Neural Stem Cells/metabolism
  4. Fulltext Growth Hormone Treatment Promotes Remote Hippocampal Plasticity after Experimental Cortical Stroke
    Sanchez-Bezanilla S, Åberg ND, Crock P, Walker FR, Nilsson M, Isgaard J, et al.
    Int J Mol Sci, 2020 Jun 26;21(12).
    PMID: 32604953 DOI: 10.3390/ijms21124563
    Cognitive impairment is common after stroke, and disturbances in hippocampal function are often involved, even in remote non-hippocampal injuries. In terms of hippocampal function, growth hormone (GH) is known to affects plasticity and cognition. We aimed to investigate whether GH treatment after an experimental cortical stroke could enhance remote hippocampal plasticity and the hippocampal-dependent visual discrimination task. C57BL6 male mice were subjected to cortical photothrombotic stroke. Stroke mice were then treated with either saline or GH at 48 h after occlusion for 28 days. We assessed learning and memory using mouse touchscreen platform for the visual discrimination task. We also evaluated markers of neural progenitor cells, synaptic plasticity and cerebrovascular remodelling in the hippocampal formation. GH treatment significantly improved the performance on visual discrimination task after stroke. We observed a concomitant increased number of bromodeoxyuridine-positive cells in the dentate gyrus of the hippocampus. We also detected increased protein levels and density of doublecortin, a neuronal precursor cells marker, as well as glutamate receptor 1 (GLuR1), a synaptic marker. These findings provide further neurobiological evidence for how GH treatment could be used to promote hippocampal plasticity in a remote region from the initial cortical injury, and thus enhance cognitive recovery after stroke.
    Matched MeSH terms: Neural Stem Cells/metabolism
  5. Fulltext Pluripotent Human embryonic stem cell derived neural lineages for in vitro modelling of enterovirus 71 infection and therapy
    Yap MS, Tang YQ, Yeo Y, Lim WL, Lim LW, Tan KO, et al.
    Virol J, 2016 Jan 06;13:5.
    PMID: 26738773 DOI: 10.1186/s12985-015-0454-6
    The incidence of neurological complications and fatalities associated with Hand, Foot & Mouth disease has increased over recent years, due to emergence of newly-evolved strains of Enterovirus 71 (EV71). In the search for new antiviral therapeutics against EV71, accurate and sensitive in vitro cellular models for preliminary studies of EV71 pathogenesis is an essential prerequisite, before progressing to expensive and time-consuming live animal studies and clinical trials.
    Matched MeSH terms: Neural Stem Cells/metabolism
  6. Collagen-coated polylactic-glycolic acid (PLGA) seeded with neural-differentiated human mesenchymal stem cells as a potential nerve conduit
    Sulong AF, Hassan NH, Hwei NM, Lokanathan Y, Naicker AS, Abdullah S, et al.
    Adv Clin Exp Med, 2014 May-Jun;23(3):353-62.
    PMID: 24979505
    Autologous nerve grafts to bridge nerve gaps pose various drawbacks. Nerve tissue engineering to promote nerve regeneration using artificial neural conduits has emerged as a promising alternative.
    Matched MeSH terms: Neural Stem Cells/metabolism
  7. Drug Encapsulated Nanoparticles for Treating Targeted Cells
    Suk KH, Gopinath SCB
    Curr Med Chem, 2017;24(30):3310-3321.
    PMID: 28464786 DOI: 10.2174/0929867324666170502122444
    BACKGROUND: Drug encapsulated nanoparticle has the potency to act as an effective antidote for various diseases. It is possible to enhance the bioavailability of drug encapsulated nanoparticle, whereby the yield is significantly higher compared to the standard formulation. The development with drug encapsulated nanoparticle has been improved drastically after demonstrating its capability of showing the enhanced thermophysical properties and stability of the drug. It is also utilized widely in cancer diagnoses, whereby the surface of the nanoparticle can be modified to enable the nanocarriers to reach the targeted location. Thus, the encapsulated nanoparticle can reveal neural stem cell differentiation due to the multifaceted nature and the biophysical cues to control the cell differentiation.

    OBJECTIVE: In this overview, different advantages of the drug encapsulated nanoparticle for the downstream applications are narrated with its appealing characteristics.

    CONCLUSION: The application of the drug encapsulated nanoparticle is unrestricted as it can be customized to the specific target cell in the living system.

    Matched MeSH terms: Neural Stem Cells/metabolism
  8. Fulltext REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease
    Meyer K, Feldman HM, Lu T, Drake D, Lim ET, Ling KH, et al.
    Cell Rep, 2019 01 29;26(5):1112-1127.e9.
    PMID: 30699343 DOI: 10.1016/j.celrep.2019.01.023
    The molecular basis of the earliest neuronal changes that lead to Alzheimer's disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD.
    Matched MeSH terms: Neural Stem Cells/metabolism
  9. The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis
    Chan EWL, Krishnansamy S, Wong C, Gan SY
    Neurotoxicology, 2019 01;70:91-98.
    PMID: 30408495 DOI: 10.1016/j.neuro.2018.11.001
    The cognitive impairment caused by Alzheimer's disease (AD) is associated with beta-amyloid (Aβ) and tau proteins, and is accompanied by inflammation. Recently, a novel inflammasome signaling pathway has been uncovered. Inflammasomes are implicated in the execution of inflammatory responses and pyroptotic death leading to neurodegeneration. Thus, the inflammasome signaling pathway could be a potential therapeutic target for AD. Neural stem cells (NSCs) are multipotent cells that can self-renew and differentiate into distinct neural cells. NSC therapy has been considered to be a promising therapeutic approach in protecting the central nervous system and restoring it following damage. However, the mechanisms involved remain unclear. The aims of this study were to investigate the protective effects of NE4C neural stem cells against microglia-mediated neurotoxicity and to explore molecular mechanisms mediating their actions. NE4C decreased the levels of caspase-1 and IL-1β, and attenuated the level of the NLRP3 inflammasome and its associated protein adapter, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) in LPS-stimulated BV2 microglial cells, possibly by regulating the phosphorylation of p38α MAPK. The conditioned media obtained from co-culture of LPS-stimulated BV2 and NE4C cells exhibited protective effects on SH-SY5Y cells against microglia-mediated neurotoxicity; this was associated with an attenuation of tau phosphorylation and amyloidogenesis and accompanied by down-regulation of GSK-3β and p38α MAPK signalling pathways. In conclusion, the present study suggested that NSC therapy could be a potential strategy against microglia-mediated neurotoxicity. NSCs regulate NLRP3 activation and IL-1β secretion, which are critical in the initiation of the inflammatory responses, hence preventing the release of neurotoxic pro-inflammatory factors by microglia. This eventually reduces tau hyperphosphylation and amyloidogenesis, possibly through the regulation of GSK-3β and p38α MAPK signalling pathways, and thus protects SH-SY5Y cells against microglia-mediated neurotoxicity.
    Matched MeSH terms: Neural Stem Cells/metabolism*
  10. Fulltext Maintenance of active chromatin states by HMGN2 is required for stem cell identity in a pluripotent stem cell model
    Garza-Manero S, Sindi AAA, Mohan G, Rehbini O, Jeantet VHM, Bailo M, et al.
    Epigenetics Chromatin, 2019 12 12;12(1):73.
    PMID: 31831052 DOI: 10.1186/s13072-019-0320-7
    BACKGROUND: Members of the HMGN protein family modulate chromatin structure and influence epigenetic modifications. HMGN1 and HMGN2 are highly expressed during early development and in the neural stem/progenitor cells of the developing and adult brain. Here, we investigate whether HMGN proteins contribute to the chromatin plasticity and epigenetic regulation that is essential for maintaining pluripotency in stem cells.

    RESULTS: We show that loss of Hmgn1 or Hmgn2 in pluripotent embryonal carcinoma cells leads to increased levels of spontaneous neuronal differentiation. This is accompanied by the loss of pluripotency markers Nanog and Ssea1, and increased expression of the pro-neural transcription factors Neurog1 and Ascl1. Neural stem cells derived from these Hmgn-knockout lines also show increased spontaneous neuronal differentiation and Neurog1 expression. The loss of HMGN2 leads to a global reduction in H3K9 acetylation, and disrupts the profile of H3K4me3, H3K9ac, H3K27ac and H3K122ac at the Nanog and Oct4 loci. At endodermal/mesodermal genes, Hmgn2-knockout cells show a switch from a bivalent to a repressive chromatin configuration. However, at neuronal lineage genes whose expression is increased, no epigenetic changes are observed and their bivalent states are retained following the loss of HMGN2.

    CONCLUSIONS: We conclude that HMGN1 and HMGN2 maintain the identity of pluripotent embryonal carcinoma cells by optimising the pluripotency transcription factor network and protecting the cells from precocious differentiation. Our evidence suggests that HMGN2 regulates active and bivalent genes by promoting an epigenetic landscape of active histone modifications at promoters and enhancers.

    Matched MeSH terms: Neural Stem Cells/metabolism
  11. ATM inhibition prevents interleukin-6 from contributing to the proliferation of glioblastoma cells after ionizing radiation
    Lim YC, Quek H, Offenhäuser C, Fazry S, Boyd A, Lavin M, et al.
    J Neurooncol, 2018 Jul;138(3):509-518.
    PMID: 29564746 DOI: 10.1007/s11060-018-2838-0
    Glioblastoma (GBM) is a highly fatal disease with a 5 year survival rate of less than 22%. One of the most effective treatment regimens to date is the use of radiotherapy which induces lethal DNA double-strand breaks to prevent tumour growth. However, recurrence occurs in the majority of patients and is in-part a result of robust radioresistance mechanisms. In this study, we demonstrate that the multifunctional cytokine, interleukin-6 (IL-6), confers a growth advantage in GBM cells but does not have the same effect on normal neural progenitor cells. Further analysis showed IL-6 can promote radioresistance in GBM cells when exposed to ionising radiation. Ablation of the Ataxia-telangiectasia mutated serine/threonine kinase that is recruited and activated by DNA double-strand breaks reverses the effect of radioresistance and re-sensitised GBM to DNA damage thus leading to increase cell death. Our finding suggests targeting the signaling cascade of DNA damage response is a potential therapeutic approach to circumvent IL-6 from promoting radioresistance in GBM.
    Matched MeSH terms: Neural Stem Cells/metabolism
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