Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single cell analyses of Amyloid-beta42 and Interleukin-4 on neural stem cell plasticity IV

ABSTRACT: Neural stem cells (NSCs) constitute the reservoir for new cells and might be harnessed for stem cell-based regenerative therapies. Zebrafish has remarkable ability to regenerate its brain by inducing NSC plasticity upon Alzheimer’s pathology. We recently identified that NSCs enhance their proliferation and neurogenic outcome in an Amyloid-beta42-based (Aβ42) experimental Alzheimer’s disease model in zebrafish brain and Interleukin-4 (IL4) is a critical molecule for inducing NSC proliferation in AD conditions. However, the mechanisms by which Aβ42 and IL4 affect NSCs remained unknown. Using single cell transcriptomics, we determined distinct subtypes of NSCs and neurons in adult zebrafish brain, identified differentially expressed genes after Aβ42 and IL4 treatments, analyzed the gene ontology and pathways that are affected by Aβ42 and IL4, and investigated how cell-cell communication is altered through secreted molecules and their receptors. Our results constitute the most extensive resource in the Alzheimer’s disease model of adult zebrafish brain, are likely to provide unique insights into how Aβ42/IL4 affects NSC plasticity and yield in novel drug targets for mobilizing neural stem cells for endogenous neuro-regeneration.

ORGANISM(S): Danio rerio

PROVIDER: GSE118599 | GEO | 2020/04/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Single cell analyses of Amyloid-beta42 and Interleukin-4 on neural stem cell plasticity I

Project description:The neural stem cell (NSC) reservoir can be harnessed for stem cell-based regenerative therapies. Zebrafish remarkably regenerate their brain by inducing NSC plasticity in a Amyloid-β-42 (Aβ42)-induced experimental Alzheimer’s disease (AD) model. Interleukin-4 (IL-4) is also critical for AD-induced NSC proliferation. However, the mechanisms of this response have remained unknown. Using single-cell transcriptomics in the adult zebrafish brain, we identify distinct subtypes of NSCs and neurons and differentially regulated pathways and their gene ontologies and investigate how cell-cell communication is altered through ligand-receptor pairs in AD conditions. Our results propose the existence of heterogeneous and spatially organized stem cell populations that react distinctly to amyloid toxicity. This resource article provides an extensive database for the molecular basis of NSC plasticity in the AD model of the adult zebrafish brain. Further analyses of stem cell heterogeneity and neuro-regenerative ability at single-cell resolution could yield drug targets for mobilizing NSCs for endogenous neuro-regeneration in humans.

2019-12-04 | GSE118577 | GEO

Interleukin-4 induces neural stem cell plasticity by antagonizing Serotonin/HTR1 signaling that suppresses BDNF/NGFRA in adult zebrafish Alzheimer's disease model

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

Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-beta42 toxicity

Project description:The immune response is an important determinant of the plasticity and neurogenic capacity of neural stem cells (NSCs) upon amyloid-beta42 (Aβ42) toxicity in Alzheimer’s disease (AD). However, the direct effects of individual immuno-modulatory effectors on NSC plasticity remain to be elucidated and are the motivation for reductionist tissue-mimetic culture experiments. Using starPEG-Heparin hydrogel system that provides a defined 3D cell-instructive neuro-microenvironment culture system, sustains high levels of proliferative and neurogenic activity of human NSCs, and recapitulates the fundamental pathological consequences of Amyloid toxicity upon Aβ42 administration, we found that the anti-inflammatory cytokine interleukin-4 (IL4) restores the plasticity and neurogenic capacity of NSCs by suppressing the Aβ42-induced kynurenic acid-producing enzyme kynurenine aminotransferase 2 (KAT2), which we also found to be upregulated in the brains of the AD model, APP/PS1dE9 mouse. Our transcriptome analyses showed that IL4 treatment restores the expression levels of NSC and cortical subtype markers. Thus, our dissective neuro-microenvironment culture revealed IL4-mediated neuroinflammatory crosstalk for human NSC plasticity and predicted a new mechanistic target for therapeutic intervention in AD. Primary (from Gestation week 21 of human fetus) and induced (adult human fibroblast-derived) neural stem cells are cultured in 2D and 3D. Next generation sequencing is performed at 3 weeks of culture.

2020-01-01 | GSE108038 | GEO

Early Stem Cell Aging in the Mature Brain

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

NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice

Project description:Transplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation is limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells (iPSCs) together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarct, neuronal death and glial scarring, and promoted the motor function recovery. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

2023-04-26 | GSE217074 | GEO

Molecular Cascade Reveals Sequential Milestones Underlying Hippocampal Neural Stem Cell Development into an Adult State

Project description:Quiescent adult neural stem cells (NSCs) in the mammalian brain arise from proliferating NSCs during development. Beyond acquisition of quiescence, an adult NSC hallmark, little is known about the process, milestones and mechanisms underlying the transition of developmental NSCs to an adult NSC state. Here we performed targeted single-cell RNA-seq analysis to reveal the molecular cascade underlying NSC development in the early postnatal mouse dentate gyrus. We identified two sequential steps, first a transition to quiescence followed by further maturation, each of which involved distinct changes in metabolic gene expression. Direct metabolic analysis uncovered distinct milestones, including an autophagy burst before NSC quiescence acquisition and cellular ROS level elevation along NSC maturation. Functionally, autophagy is important for the NSC transition to quiescence during early postnatal development. Together, our study reveals a multi-step process with defined milestones underlying establishment of the adult NSC pool in the mammalian brain.

2024-06-05 | GSE232833 | GEO

Interleukin-4/STAT6 signaling impairs the survival of mouse astroglia in vivo but not in vitro

Project description:Neurogenesis is limited in mammalian brains and Alzheimer’s disease conditions further reduce the neurogenic output. Recent findings suggest that reduced neurogenesis could be one of the reasons underlying the exacerbated neuropathology in humans, and restoring the neural stem cell proliferation and neurogenesis could help circumventing some pathological aspects of Alzheimer’s disease. We recently identified Interleukin-4/STAT6 signaling as a neuron-glia crosstalk mechanism that enables glial proliferation and neurogenesis in adult zebrafish brain and 3D cultures of human astroglia, which manifest neurogenic properties. In this study, we tested whether activating IL4/STAT6 signaling in adult mouse astroglia would enhance cell proliferation and neurogenesis in health and disease conditions. By using single cell sequencing in APP/PS1dE9 mouse model of AD, we found that IL4 receptor (Il4r) is not expressed in mouse astroglia. Lentivirus-mediated expression of IL4R or constitutively active STAT6V impaired the survival capacity of mouse astroglia in vivo but not in vitro. Our findings suggest that adult mouse brain generates a non-permissive environment that dictates a negative effect of IL4 signaling on astroglial survival and neurogenic properties in contrast to zebrafish brains and in vitro mammalian cell cultures.

2020-03-23 | GSE140793 | GEO

Ependyma-expressed CCN1 restricts the size of the neural stem cell pool in the adult ventricular-subventricular zone

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

Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury

Project description:Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain. Single cell RNAseq of cells isolated from their in vivo niche in the subventricular zone, Striatum and Cortex during homeostasis as well as following ischemic injury. In total 272 single cells. (<WT>: homeostasis samples; <Ischemic_injured> and <Ischemic_injured_and_Interferon_gamma_knockout>: samples following ischemic injuried).

2015-07-31 | E-GEOD-67833 | biostudies-arrayexpress

Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury

2015-07-31 | GSE67833 | GEO