Search Results (14)

In the adult mammalian brain, neurons are produced from neural stem cells (NSCs) residing in two niches—the subventricular zone (SVZ), which forms the lining of the lateral ventricles, and the subgranular zone in the hippocampus. Epigenetic mechanisms contribute to maintaining distinct cell fates by suppressing gene expression that is required for deciding alternate cell fates. Several histone deacetylase (HDAC) inhibitors can affect adult neurogenesis in vivo. However, data regarding the role of specific HDACs in cell fate decisions remain limited. Herein, we demonstrate that HDAC8 participates in the regulation of the proliferation and differentiation of NSCs/neural progenitor cells (NPCs) in the adult mouse SVZ. Specific knockout of Hdac8 in NSCs/NPCs inhibited proliferation and neural differentiation. Treatment with the selective HDAC8 inhibitor PCI-34051 reduced the neurosphere size in cultures from the SVZ of adult mice. Further transcriptional datasets revealed that HDAC8 inhibition in adult SVZ cells disturbs biological processes, transcription factor networks, and key regulatory pathways. HDAC8 inhibition in adult SVZ neurospheres upregulated the cytokine-mediated signaling and downregulated the cell cycle pathway. In conclusion, HDAC8 participates in the regulation of in vivo proliferation and differentiation of NSCs/NPCs in the adult SVZ, which provides insights into the underlying molecular mechanisms. Full article

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS), consisting of heterogeneous clinical courses varying from relapsing-remitting MS (RRMS), in which disability is linked to bouts of inflammation, to progressive disease such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), in which neurological disability is thought to be linked to neurodegeneration. As a result, successful therapeutics for progressive MS likely need to have both anti-inflammatory and direct neuroprotective properties. The modulation of sphingosine-1-phosphate (S1P) receptors has been implicated in neuroprotection in preclinical animal models. Siponimod/BAF312, the first oral treatment approved for SPMS, may have direct neuroprotective benefits mediated by its activity as a selective (S1P receptor 1) S1P1 and (S1P receptor 5) S1P5 modulator. We showed that S1P1 was mainly present in cortical neurons in lesioned areas of the MS brain. To gain a better understanding of the neuroprotective effects of siponimod in MS, we used both rat neurons and human-induced pluripotent stem cell (iPSC)-derived neurons treated with the neuroinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Cell survival/apoptotic assays using flow cytometry and IncuCyte live cell analyses showed that siponimod decreased TNF-α induced neuronal cell apoptosis in both rat and human iPSCs. Importantly, a transcriptomic analysis revealed that mitochondrial oxidative phosphorylation, NFκB and cytokine signaling pathways contributed to siponimod’s neuroprotective effects. Our data suggest that the neuroprotection of siponimod/BAF312 likely involves the relief of oxidative stress in neuronal cells. Further studies are needed to explore the molecular mechanisms of such interactions to determine the relationship between mitochondrial dysfunction and neuroinflammation/neurodegeneration. Full article

Neural progenitor cells (NPCs) are multipotent neural stem cells (NSCs) capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. In the postnatal/adult brain, NPCs are primarily located in the subventricular zone (SVZ) of the lateral ventricles (LVs) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). There is evidence that NPCs are also present in the postnatal/adult hypothalamus, a highly conserved brain region involved in the regulation of core homeostatic processes, such as feeding, metabolism, reproduction, neuroendocrine integration and autonomic output. In the rodent postnatal/adult hypothalamus, NPCs mainly comprise different subtypes of tanycytes lining the wall of the 3^rd ventricle. In the postnatal/adult human hypothalamus, the neurogenic niche is constituted by tanycytes at the floor of the 3^rd ventricle, ependymal cells and ribbon cells (showing a gap-and-ribbon organization similar to that in the SVZ), as well as suprachiasmatic cells. We speculate that in the postnatal/adult human hypothalamus, neurogenesis occurs in a highly complex, exquisitely sophisticated neurogenic niche consisting of at least four subniches; this structure has a key role in the regulation of extrahypothalamic neurogenesis, and hypothalamic and extrahypothalamic neural circuits, partly through the release of neurotransmitters, neuropeptides, extracellular vesicles (EVs) and non-coding RNAs (ncRNAs). Full article

Pluripotent neural stem or progenitor cells (NSC/NPC) have been reported in the brains of adult preclinical models for decades, as have mesenchymal stem/stromal cells (MSC) been reported in a variety of tissues from adults. Based on their in vitro capabilities, these cell types have been used extensively in attempts to repair/regenerate brain and connective tissues, respectively. In addition, MSC have also been used in attempts to repair compromised brain centres. However, success in treating chronic neural degenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and others with NSC/NPC has been limited, as have the use of MSC in the treatment of chronic osteoarthritis, a condition affecting millions of individuals. However, connective tissues are likely less complex than neural tissues regarding cell organization and regulatory integration, but some insights have been gleaned from the studies regarding connective tissue healing with MSC that may inform studies attempting to initiate repair and regeneration of neural tissues compromised acutely or chronically by trauma or disease. This review will discuss the similarities and differences in the applications of NSC/NPC and MSC, where some lessons have been learned, and potential approaches that could be used going forward to enhance progress in the application of cellular therapy to facilitate repair and regeneration of complex structures in the brain. In particular, variables that may need to be controlled to enhance success are discussed, as are different approaches such as the use of extracellular vesicles from stem/progenitor cells that could be used to stimulate endogenous cells to repair the tissues rather than consider cell replacement as the primary option. Caveats to all these efforts relate to whether cellular repair initiatives will have long-term success if the initiators for neural diseases are not controlled, and whether such cellular initiatives will have long-term success in a subset of patients if the neural diseases are heterogeneous and have multiple etiologies. Full article

Advances in the regenerative stem cell field have propelled the generation of tissue-specific cells in the culture dish for subsequent transplantation, drug screening purposes, or the elucidation of disease mechanisms. One major obstacle is the heterogeneity of these cultures, in which the tissue-specific cells of interest usually represent only a fraction of all generated cells. Direct identification of the cells of interest and the ability to specifically isolate these cells in vitro is, thus, highly desirable for these applications. The type VI intermediate filament protein NESTIN is widely used as a marker for neural stem/progenitor cells (NSCs/NPCs) in the developing and adult central and peripheral nervous systems. Applying CRISPR-Cas9 technology, we have introduced a red fluorescent reporter (mScarlet) into the NESTIN (NES) locus of a human induced pluripotent stem cell (hiPSC) line. We describe the generation and characterization of NES-mScarlet reporter hiPSCs and demonstrate that this line is an accurate reporter of NSCs/NPCs during their directed differentiation into human midbrain dopaminergic (mDA) neurons. Furthermore, NES-mScarlet hiPSCs can be used for direct identification during live cell imaging and for flow cytometric analysis and sorting of red fluorescent NSCs/NPCs in this paradigm. Full article

Glioblastoma (GBM) is the most aggressive among the neurological tumors. At present, no chemotherapy or radiotherapy regimen is associated with a positive long-term outcome. In the majority of cases, the tumor recurs within 32–36 weeks of initial treatment. The recent discovery that Zika virus (ZIKV) has an oncolytic action against GBM has brought hope for the development of new therapeutic approaches. ZIKV is an arbovirus of the Flaviviridae family, and its infection during development has been associated with central nervous system (CNS) malformations, including microcephaly, through the targeting of neural stem/progenitor cells (NSCs/NPCs). This finding has led various groups to evaluate ZIKV’s effects against glioblastoma stem cells (GSCs), supposedly responsible for GBM onset, progression, and therapy resistance. While preliminary data support ZIKV tropism toward GSCs, a more accurate study of ZIKV mechanisms of action is fundamental in order to launch ZIKV-based clinical trials for GBM patients. Full article

The considerable post-traumatic brain recovery in fishes makes them a useful model for studying the mechanisms that provide reparative neurogenesis, which is poorly represented in mammals. After a mechanical injury to the telencephalon in adult fish, lost neurons are actively replaced due to the proliferative activity of neuroepithelial cells and radial glia in the neurogenic periventricular zone. However, it is not enough clear which signaling mechanisms are involved in the activation of adult neural stem cells (aNSC) after the injury (reactive proliferation) and in the production of new neurons (regenerative neurogenesis) from progenitor cells (NPC). In juvenile Pacific salmon, the predominant type of NSCs in the telencephalon are neuroepithelial cells corresponding to embryonic NSCs. Expression of glutamine synthetase (GS), a NSC molecular marker, was detected in the neuroepithelial cells of the pallium and subpallium of juvenile chum salmon, Oncorhynchus keta. At 3 days after a traumatic brain injury (TBI) in juvenile chum salmon, the GS expression was detected in the radial glia corresponding to aNSC in the pallium and subpallium. The maximum density of distribution of GS⁺ radial glia was found in the dorsal pallial region. Hydrogen sulfide (H₂S) is a proneurogenic factor that reduces oxidative stress and excitotoxicity effects, along with the increased GS production in the brain cells of juvenile chum salmon. In the fish brain, H₂S producing by cystathionine β-synthase in neurogenic zones may be involved in maintaining the microenvironment that provides optimal conditions for the functioning of neurogenic niches during constitutive neurogenesis. After injury, H₂S can determine cell survivability, providing a neuroprotective effect in the area of injury and reducing the process of glutamate excitotoxicity, acting as a signaling molecule involved in changing the neurogenic environment, which leads to the reactivation of neurogenic niches and cell regeneration programs. The results of studies on the control of the expression of regulatory Sonic Hedgehog genes (Shh) and the transcription factors Paired Box2 (Pax2) regulated by them are still insufficient. A comparative analysis of Pax2 expression in the telencephalon of intact chum salmon showed the presence of constitutive patterns of Pax2 expression in neurogenic areas and non-neurogenic parenchymal zones of the pallium and subpallium. After mechanical injury, the patterns of Pax2 expression changed, and the amount of Pax2⁺ decreased (p < 0.05) in lateral (Dl), medial (Dm) zones of the pallium, and the lateral zone (Vl) of the subpallium compared to the control. We believe that the decrease in the expression of Pax2 may be caused by the inhibitory effect of the Pax6 transcription factor, whose expression in the juvenile salmon brain increases upon injury. Full article

Fish are a convenient model for the study of reparative and post-traumatic processes of central nervous system (CNS) recovery, because the formation of new cells in their CNS continues throughout life. After a traumatic injury to the cerebellum of juvenile masu salmon, Oncorhynchus masou, the cell composition of the neurogenic zones containing neural stem cells (NSCs)/neural progenitor cells (NPCs) in the acute period (two days post-injury) changes. The presence of neuroepithelial (NE) and radial glial (RG) neuronal precursors located in the dorsal, lateral, and basal zones of the cerebellar body was shown by the immunohistochemical (IHC) labeling of glutamine synthetase (GS). Progenitors of both types are sources of neurons in the cerebellum of juvenile O. masou during constitutive growth, thus, playing an important role in CNS homeostasis and neuronal plasticity during ontogenesis. Precursors with the RG phenotype were found in the same regions of the molecular layer as part of heterogeneous constitutive neurogenic niches. The presence of neuroepithelial and radial glia GS+ cells indicates a certain proportion of embryonic and adult progenitors and, obviously, different contributions of these cells to constitutive and reparative neurogenesis in the acute post-traumatic period. Expression of nestin and vimentin was revealed in neuroepithelial cerebellar progenitors of juvenile O. masou. Patterns of granular expression of these markers were found in neurogenic niches and adjacent areas, which probably indicates the neurotrophic and proneurogenic effects of vimentin and nestin in constitutive and post-traumatic neurogenesis and a high level of constructive metabolism. No expression of vimentin and nestin was detected in the cerebellar RG of juvenile O. masou. Thus, the molecular markers of NSCs/NPCs in the cerebellum of juvenile O. masou are as follows: vimentin, nestin, and glutamine synthetase label NE cells in intact animals and in the post-traumatic period, while GS expression is present in the RG of intact animals and decreases in the acute post-traumatic period. A study of distribution of cystathionine β-synthase (CBS) in the cerebellum of intact young O. masou showed the expression of the marker mainly in type 1 cells, corresponding to NSCs/NCPs for other molecular markers. In the post-traumatic period, the number of CBS+ cells sharply increased, which indicates the involvement of H₂S in the post-traumatic response. Induction of CBS in type 3 cells indicates the involvement of H₂S in the metabolism of extracellular glutamate in the cerebellum, a decrease in the production of reactive oxygen species, and also arrest of the oxidative stress development, a weakening of the toxic effects of glutamate, and a reduction in excitotoxicity. The obtained results allow us to consider H₂S as a biologically active substance, the numerous known effects of which can be supplemented by participation in the processes of constitutive neurogenesis and neuronal regeneration. Full article

Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and ex vivo DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of Id2 (inhibitor of differentiation 2) and Sox2 (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure. Full article

Neurogenesis is the process by which functional new neurons are generated from the neural stem cells (NSCs) or neural progenitor cells (NPCs). Increasing lines of evidence show that neurogenesis impairment is involved in different neurological illnesses, including mood disorders, neurogenerative diseases, and central nervous system (CNS) injuries. Since reversing neurogenesis impairment was found to improve neurological outcomes in the pathological conditions, it is speculated that modulating neurogenesis is a potential therapeutic strategy for neurological diseases. Among different modulators of neurogenesis, melatonin is a particularly interesting one. In traditional understanding, melatonin controls the circadian rhythm and sleep–wake cycle, although it is not directly involved in the proliferation and survival of neurons. In the last decade, it was reported that melatonin plays an important role in the regulation of neurogenesis, and thus it may be a potential treatment for neurogenesis-related disorders. The present review aims to summarize and discuss the recent findings regarding the protective effects of melatonin on the neurogenesis impairment in different neurological conditions. We also address the molecular mechanisms involved in the actions of melatonin in neurogenesis modulation. Full article

Glioblastoma (GBM) is a fast-growing type of malignant primary brain tumor. To explore the mechanisms in GBM, complex biological networks are used to reveal crucial changes among different biological states, which reflect on the development of living organisms. It is critical to discover the kernel differential subgraph (KDS) that leads to drastic changes. However, identifying the KDS is similar to the Steiner Tree problem that is an NP-hard problem. In this paper, we developed a criterion to explore the KDS (CKDS), which considered the connectivity and scale of KDS, the topological difference of nodes and function relevance between genes in the KDS. The CKDS algorithm was applied to simulated datasets and three single-cell RNA sequencing (scRNA-seq) datasets including GBM, fetal human cortical neurons (FHCN) and neural differentiation. Then we performed the network topology and functional enrichment analyses on the extracted KDSs. Compared with the state-of-art methods, the CKDS algorithm outperformed on simulated datasets to discover the KDSs. In the GBM and FHCN, seventeen genes (one biomarker, nine regulatory genes, one driver genes, six therapeutic targets) and KEGG pathways in KDSs were strongly supported by literature mining that they were highly interrelated with GBM. Moreover, focused on GBM, there were fifteen genes (including ten regulatory genes, three driver genes, one biomarkers, one therapeutic target) and KEGG pathways found in the KDS of neural differentiation process from activated neural stem cells (aNSC) to neural progenitor cells (NPC), while few genes and no pathway were found in the period from NPC to astrocytes (Ast). These experiments indicated that the process from aNSC to NPC is a key differentiation period affecting the development of GBM. Therefore, the CKDS algorithm provides a unique perspective in identifying cell-type-specific genes and KDSs. Full article

The proliferation of neural stem cells (NSCs)/neuronal precursor cells (NPCs) and the occurrence of postmitotic neuroblasts in the mesencephalic tegmentum of intact juvenile chum salmon, Oncorhynchus keta, and at 3 days after a tegmental injury, were studied by immunohistochemical labeling. BrdU+ constitutive progenitor cells located both in the periventricular matrix zone and in deeper subventricular and parenchymal layers of the brain are revealed in the tegmentum of juvenile chum salmon. As a result of traumatic damage to the tegmentum, the proliferation of resident progenitor cells of the neuroepithelial type increases. Nestin-positive and vimentin-positive NPCs and granules located in the periventricular and subventricular matrix zones, as well as in the parenchymal regions of the tegmentum, are revealed in the mesencephalic tegmentum of juvenile chum salmon, which indicates a high level of constructive metabolism and constitutive neurogenesis. The expression of vimentin and nestin in the extracellular space, as well as additionally in the NSCs and NPCs of the neuroepithelial phenotype, which do not express nestin in the control animals, is enhanced during the traumatic process. As a result of the proliferation of such cells in the post-traumatic period, local Nes+ and Vim+ NPCs clusters are formed and become involved in the reparative response. Along with the primary traumatic lesion, which coincides with the injury zone, additional Nes+ and Vim+ secondary lesions are observed to form in the adjacent subventricular and parenchymal zones of the tegmentum. In the lateral tegmentum, the number of doublecortin-positive cells is higher compared to that in the medial tegmentum, which determines the different intensities and rates of neuronal differentiation in the sensory and motor regions of the tegmentum, respectively. In periventricular regions remote from the injury, the expression of doublecortin in single cells and their groups significantly increases compared to that in the damage zone. Full article

Regeneration of injuries occurring in the central nervous system, particularly spinal cord injuries (SCIs), is extremely difficult. The complex pathological events following a SCI often restrict regeneration of nervous tissue at the injury site and frequently lead to irreversible loss of motor and sensory function. Neural stem/progenitor cells (NSCs/NPCs) possess neuroregenerative and neuroprotective features, and transplantation of such cells into the site of damaged tissue is a promising stem cell-based therapy for SCI. However, NSC/NPCs have mostly been induced from embryonic stem cells or fetal tissue, leading to ethical concerns. The pioneering work of Yamanaka and colleagues gave rise to the technology to induce pluripotent stem cells (iPSCs) from somatic cells, overcoming these ethical issues. The advent of iPSCs technology has meant significant progress in the therapy of neurodegenerative disease and nerve tissue damage. A number of published studies have described the successful differentiation of NSCs/NPCs from iPSCs and their subsequent engraftment into SCI animal models, followed by functional recovery of injury. The aim of this present review is to summarize various iPSC- NPCs differentiation methods, SCI modelling, and the current status of possible iPSC- NPCs- based therapy of SCI. Full article

Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases. Neurotrophic factors are well known for their positive effects on the proliferation/differentiation of both embryonic and adult neural stem/progenitor cells (NSCs/NPCs). Especially, brain-derived neurotrophic factor (BDNF) has been extensively investigated because of its roles in the differentiation/maturation of NSCs/NPCs. On the other hand, recent evidence indicates a negative impact of the stress hormone glucocorticoids (GCs) on the cell fate of NSCs/NPCs, which is also related to the pathophysiology of brain diseases, such as depression and autism spectrum disorder. Furthermore, studies including ours have demonstrated functional interactions between neurotrophic factors and GCs in neural events, including neurogenesis. In this review, we show and discuss relationships among the behaviors of NSCs/NPCs, BDNF, and GCs. Full article