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Analyzing human neural stem cell ontogeny by consecutive isolation of Notch active neural progenitors

ABSTRACT: Decoding heterogeneity of pluripotent stem cell (PSC)-derived neural progeny is fundamental for revealing the origin of diverse progenitors, for defining their lineages, and for identifying fate determinants driving transition through distinct potencies. Here we prospectively isolated consecutively appearing PSC-derived primary progenitors based on their Notch activation state. We first isolate early neuroepithelial cells and show their broad Notch-dependent developmental and proliferative potential. Neuroepithelial cells further yield successive Notch-dependent functional primary progenitors, from early and mid neurogenic radial glia and their derived basal progenitors, to gliogenic radial glia and adult-like neural progenitors, together recapitulating hallmarks of neural stem cell (NSC) ontogeny. Gene expression profiling reveals dynamic stage specific transcriptional patterns that may link development of distinct progenitor identities through Notch activation. Our observations provide a platform for characterization and manipulation of distinct progenitor cell types amenable for developing streamlined neural lineage specification paradigms for modeling development in health and disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65369 | GEO | 2015/02/18

SECONDARY ACCESSION(S): PRJNA273811

REPOSITORIES: GEO

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Analyzing human neural stem cell ontogeny by consecutive isolation of Notch active neural progenitors

Project description:Decoding heterogeneity of pluripotent stem cell (PSC)-derived neural progeny is fundamental for revealing the origin of diverse progenitors, for defining their lineages, and for identifying fate determinants driving transition through distinct potencies. Here we prospectively isolated consecutively appearing PSC-derived primary progenitors based on their Notch activation state. We first isolate early neuroepithelial cells and show their broad Notch-dependent developmental and proliferative potential. Neuroepithelial cells further yield successive Notch-dependent functional primary progenitors, from early and mid neurogenic radial glia and their derived basal progenitors, to gliogenic radial glia and adult-like neural progenitors, together recapitulating hallmarks of neural stem cell (NSC) ontogeny. Gene expression profiling reveals dynamic stage specific transcriptional patterns that may link development of distinct progenitor identities through Notch activation. Our observations provide a platform for characterization and manipulation of distinct progenitor cell types amenable for developing streamlined neural lineage specification paradigms for modeling development in health and disease. Human embryonic stem cells (hESCs) H9 were differentiated into 5 distinct populations of neural precursor cells (NPCs) over a time course of 200 days. Each neural precursor populations was then sorted for HES5 expression based on a GFP-HES5 reporter. Both the HES5 positive and HES5 negative populations were then subjected to microarray profiling in singlicate, as well as the hESCs using GeneChipPrimeView Human Gene Expression Array

2015-02-18 | E-GEOD-65369 | biostudies-arrayexpress

RNA Expression profiling of primary mouse Neural Plate Border Stem Cells, differentiated progeny and biological controls

Project description:We describe a so far uncharacterized, embryonic and self-renewing Neural Plate Border Stem Cell (NBSC) population with the capacity to differentiate into central nervous and neural crest lineages. NBSCs can be obtained by neural transcription factor-mediated reprogramming (BRN2, SOX2, KLF4, and ZIC3) of human adult dermal fibroblasts and peripheral blood cells (induced Neural Plate Border Stem Cells, iNBSCs) or by directed differentiation from human induced pluripotent stem cells. Moreover, human (i)NBSCs share molecular and functional features with an endogenous NBSC population isolated from neural folds of E8.5 mouse embryos. Upon differentiation, iNBSCs give rise to either (1) radial glia-type stem cells, dopaminergic and serotonergic neurons, motoneurons, astrocytes, and oligodendrocytes or (2) cells from the neural crest lineage. Here we provide array-based expression data of primary mouse Neural Plate Border Stem Cells (pNBSCs) derived from E8.5 mouse embryos and radial glia-type stem cells and neural crest progenitors derived thereof. The data provided reveal that pNBSCs can be directed into defined neural cell types of the CNS- and neural crest lineage.

2018-12-20 | E-MTAB-5805 | biostudies-arrayexpress

A robust single primate neuroepithelial cell clonal expansion system for neural tube development and disease studies

Project description:Developing a model of primate neural tube (NT) development is important to promote many NT disorder studies in model organisms. Here, we report a robust and stable system to allow for clonal expansion of single monkey neuroepithelial stem cells (NESCs) to develop into miniature NT-like structures. Single NESCs can produce functional neurons in vitro, survive and extensively regenerate neuron axons in monkey brain. NT formation and NESC maintenance depend on high metabolism activity and Wnt signaling. NESCs are regionally restricted into a telencephalic fate. Moreover, single NESCs can turn into radial glial progenitors (RGPCs). The transition is accurately regulated by Wnt signaling through regulation of Notch signaling and adhesion molecules. Finally, using the â??NESC-TO-NTsâ?? system, we model the functions of folic acid (FA) on NT closure and demonstrate FA can regulate multiple mechanisms to prevent NT defects. Together, our system is ideal for studying NT development and diseases. compare gene expression profiles in monkey neuroepithelial stem cells (NESCs), newly converted radial glial progenitor cells (RPGCs) from NESCs and differentiated neurons from NESCs

2015-11-21 | E-GEOD-73892 | biostudies-arrayexpress

Cell-to-cell adhesion and neurogenesis in human cortical development: a study comparing 2D monolayers with 3D organoid cultures

Project description:Organoids (ORG) are increasingly used as models of cerebral cortical development. Here we compared transcriptome and cellular phenotypes between ORG and monolayers (MON) generated in parallel from three biologically distinct iPSC lines. Multiple read-outs revealed increased proliferation in MON, which was caused by increased integrin signaling. MON also exhibited altered radial glia polarity, global suppression of Notch signaling and impaired generation of intermediate progenitors (INP), outer radial glia (oRG) and cortical neurons, which were all partially reversed by reaggregation of dissociated cells into organoids. Network analyses revealed co-clustering of cell adhesion, Notch- related transcripts their transcriptional regulators in a module strongly downregulated in MON. The data suggest that cortical ORG, with respect to MON, initiates more efficient Notch signaling in ventricular radial glia owing to preserved cell adhesion, resulting in subsequent generation of INP and oRG, in a sequence that better recapitulates the evolution of the cortical ontogenetic process.

2020-01-01 | GSE134216 | GEO

RNA Expression profiling of human induced Neural Plate Border Stem Cells, Neural Plate Border Stem Cell progeny and biological controls

Project description:We describe a so far uncharacterized, embryonic and self-renewing Neural Plate Border Stem Cell (NBSC) population with the capacity to differentiate into central nervous and neural crest lineages. NBSCs can be obtained by neural transcription factor-mediated reprogramming (BRN2, SOX2, KLF4, and ZIC3) of human adult dermal fibroblasts and peripheral blood cells (induced Neural Plate Border Stem Cells, iNBSCs) or by directed differentiation from human induced pluripotent stem cells (NBSCs). Moreover, human (i)NBSCs share molecular and functional features with an endogenous NBSC population isolated from neural folds of E8.5 mouse embryos. Upon differentiation, iNBSCs give rise to either (1) radial glia-type stem cells, dopaminergic and serotonergic neurons, motoneurons, astrocytes, and oligodendrocytes or (2) cells from the neural crest lineage. Here we provide array-based expression data of (i)NBSCs and CNS- and neural crest progeny derived thereof. The former comprise radial glia-type stem cells, while the latter are neural crest and mesenchymal stem cell-like cells. The data provided reveal that (i)NBSCs can be directed into defined neural lineages and that iNBSCs pass through successive developmental stages. These data support the notion that it is possible to reprogram human adult cells into expandable, multipotent NBSCs that define a novel embryonic neural stem cell population in human and mouse.

2018-12-20 | E-MTAB-5804 | biostudies-arrayexpress

GABAA receptors and mother-derived taurine regulate neural progenitor cells specification in the mouse developing cortex

Project description:The precise temporal regulation of the cellular properties of neural progenitor cells (NPCs) is essential for the histogenesis of the cerebral cortex. Neuroepithelial cells, the primary NPCs, transit to radial glia with astroglial properties. To coincide with this transition, NPCs start to differentiate into neurons, undergoing a switch from symmetric to asymmetric cell division. After the onset of neurogenesis, NPCs produce layer-specific neurons in a defined order. Here, we show that GABAA receptors and taurine are involved in this regulatory mechanism. Fetal exposure to GABAA blockers suppressed the transition to radial glia, the switch to asymmetric division and the differentiation into upper-layer neurons. Fetal exposure to GABAA positive modulators caused the opposite effects. Ca2+ imaging studies showed that NPCs principally responded to taurine, but not GABA, which is derived principally from mothers, before E13 via picrotoxin-sensitive receptors. Fetal exposure to GABAA receptor modulators resulted in considerable alterations in offspring behavior.

2016-10-31 | GSE77648 | GEO

Transcription profiling of mouse functionally distinct radial glial subsets

Project description:Since the discovery of radial glia as the source of neurons, their heterogeneity in regard to neurogenesis has been described by clonal and time-lapse analysis in vitro. However, the molecular determinants specifying neurogenic radial glia differently from radial glia that mostly self-renew remain ill-defined. Here, we isolated two radial glial subsets that co-exist at mid-neurogenesis in the developing cerebral cortex and their immediate progeny. While one subset generates neurons directly, the other is largely non-neurogenic but also gives rise to Tbr2-positive basal precursors, thereby contributing indirectly to neurogenesis. Isolation of ; these distinct radial glia subtypes allowed determining interesting differences in their transcriptome. These transcriptomes were also strikingly different from the transcriptome of radial glia isolated at the end of neurogenesis. This analysis therefore identifies, for the first time, the lineage origin of basal progenitors and the molecular differences of this lineage in comparison to directly neurogenic and gliogenic radial glia. Experiment Overall Design: Comparison of radial glial subtypes

2008-06-18 | E-GEOD-8034 | biostudies-arrayexpress

FASN-dependent de novo lipogenesis is required for brain development

Project description:Fate and behaviour of neural progenitor cells is tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells, govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multi-enzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors (APs) and reduced progenitor proliferation. Further, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell (ESC)-derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity and progenitor expansion in the developing human forebrain. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor cell polarity and lipid metabolism.

2022-01-14 | PXD026110 | Pride

REST Couples Loss of Pluripotency with Neural Induction and Neural Differentiation

Project description:Neural differentiation of embryonic stem cells (ESCs) requires coordinated repression of the pluripotency regulatory programme and reciprocal activation of the neurogenic regulatory programme. Upon neural induction, ESCs rapidly repress expression of pluripotency genes followed by staged activation of neural progenitor and differentiated neuronal and glial genes. The transcriptional factors that underlie pluripotency are partially characterized, whereas those underlying neural induction are much less explored, and the factors that coordinate these two developmental programs are completely unknown. One transcription factor, REST (RE1 silencing transcription factor), has been linked with terminal differentiation of neural progenitors, and more recently and controversially, with control of pluripotency. Here, we show that in the absence of REST, coordination of pluripotency and neural induction is lost and there is a resultant delay in repression of pluripotency genes and a precocious activation of both neural progenitor and differentiated neuronal and glial genes. Further, we show that REST is not required for production of radial glia-like progenitors but is required for their subsequent maintenance and differentiation into neurons, oligodendrocytes and astrocytes. We propose that REST acts as a regulatory hub that coordinates timely repression of pluripotency with neural induction and neural differentiation. We have investigated the role of REST in the coupling of pluripotency and neural induction and neurogenesis using Rest-null mouse ESCs (mESCs) in conjunction with a novel mESC neural differentiation protocol. Differential expression between Rest-null ESCs and controls was tested using Illumina Mouse Ref-8 v2 BeadArray technology. Three replicates were used for Rest-null and three for control. Data analysis was performed using Bioconductor libraries beadarray and limma.

2011-12-08 | E-GEOD-34244 | biostudies-arrayexpress

A robust single primate neuroepithelial cell clonal expansion system for neural tube development and disease studies

Project description:Developing a model of primate neural tube (NT) development is important to promote many NT disorder studies in model organisms. Here, we report a robust and stable system to allow for clonal expansion of single monkey neuroepithelial stem cells (NESCs) to develop into miniature NT-like structures. Single NESCs can produce functional neurons in vitro, survive and extensively regenerate neuron axons in monkey brain. NT formation and NESC maintenance depend on high metabolism activity and Wnt signaling. NESCs are regionally restricted into a telencephalic fate. Moreover, single NESCs can turn into radial glial progenitors (RGPCs). The transition is accurately regulated by Wnt signaling through regulation of Notch signaling and adhesion molecules. Finally, using the “NESC-TO-NTs” system, we model the functions of folic acid (FA) on NT closure and demonstrate FA can regulate multiple mechanisms to prevent NT defects. Together, our system is ideal for studying NT development and diseases.

2015-11-21 | GSE73892 | GEO

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