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Signal requirement for cortical potential of transplantable human neuroepithelial stem cells

ABSTRACT: The cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Initial expansion of the progenitor cell pool is followed by the generation of neurons of all the cortical layers and later, astrocytes and oligodendrocytes. However, the regulatory pathways that control the expansion and maintenance of the neuroepithelial progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs) in vitro without the loss of developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-b1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate to lower and upper layer cortical neurons both in vitro and in vivo. Identifying the mechanisms that drive the self-renewal and fate of cNESCs decision of neuroepithelial stem cells is key to developing new stem cell-based therapeutic approaches to treat neurological conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184081 | GEO | 2022/02/04

REPOSITORIES: GEO

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Signal requirement for cortical potential of transplantable human neuroepithelial stem cells [array]

Project description:The cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Initial expansion of the progenitor cell pool is followed by the generation of neurons of all the cortical layers and later, astrocytes and oligodendrocytes. However, the regulatory pathways that control the expansion and maintenance of the neuroepithelial progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs) in vitro without the loss of developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-b1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate to lower and upper layer cortical neurons both in vitro and in vivo. Identifying the mechanisms that drive the self-renewal and fate of cNESCs decision of neuroepithelial stem cells is key to developing new stem cell-based therapeutic approaches to treat neurological conditions. In this study, we performed Oxford Nanopore technologies long-read RNA-sequencing (lrRNA-seq) of human cNESCs and of the human embryonic stem cells used to generate them. Two hESC cell lines were differentiated to cNESCs, which were then maintained in either six factors (6F : BMPRi, TGFBRi, GSK3i, FGF, TANKYRASEi, AKTi) or 4 factors (6F-2F : BMPRi, TGFBRi, GSK3i, FGF). All samples (hESCs, cNESCs in 6 factors, cNESCs in 4 factors) are submitted to lrRNA-seq as duplicates.

2022-02-04 | GSE185258 | GEO

Signal requirement for cortical potential of transplantable human neuroepithelial stem cells

Project description:Signal requirement for cortical potential of transplantable human neuroepithelial stem cells

| PRJNA763125 | ENA

Signal requirement for cortical potential of transplantable human neuroepithelial stem cells [array]

Project description:Signal requirement for cortical potential of transplantable human neuroepithelial stem cells [array]

| PRJNA768415 | ENA

Generation of human cerebral organoids with a structured outer subventricular zone

Project description:Outer radial glia (oRG) emerged during mammalian evolution as cortical progenitor cells that directly support the development of an enlarged outer subventricular zone (oSVZ) and, in turn, the expansion of the neocortex. The in vitro generation of oRG is essential to model and investigate the underlying mechanisms of human neocortex development and expansion. By activating the STAT3 pathway using LIF, which is not produced in guided cortical organoids, we developed a cerebral organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The structured oSVZ is composed of progenitor cells expressing specific oRG markers such as GFAP, LIFR, HOPX and closely matching human oRG in vivo. In this microenvironment, cortical neurons showed faster maturation with enhanced metabolic and functional activity. Incorporation of hPSC-derived brain vascular LIF-producing pericytes in cerebral organoids mimicked the effects of LIF treatment. These data indicate that the cellular complexity of the cortical microenvironment, including cell types of the brain vasculature, favors the appearance of oRG and provides a platform to routinely study oRG in hPSC-derived brain organoids.

2024-04-15 | GSE224346 | GEO

Differential expression levels of Sox9 in early neocortical radial glial cells regulate the decision between stem cell maintenance and differentiation

Project description:Radial glial progenitor cells (RGCs) in the dorsal forebrain directly or indirectly produce excitatory projection neurons and macroglia of the neocortex. Recent evidence shows that the pool of RGCs is more heterogeneous than originally thought and that progenitor subpopulations can generate particular neuronal cell types. Using single cell RNA sequencing, we have studied gene expression patterns of two subtypes of RGCs that differ in their neurogenic behavior. One progenitor type rapidly produces postmitotic neurons, whereas the second progenitor remains relatively quiescence before generating neurons. We have identified candidate genes that are differentially expressed between these RGCs progenitor subtypes, including the transcription factor Sox9. Using in utero electroporation, we demonstrate that elevated Sox9 expression in progenitors prevents RGC division and leads to the generation of upper-layer cortical neurons from these progenitors at later ages. Our data thus reveal molecular differences between cortical progenitors with different neurogenic behavior and indicates that Sox9 is critical for the maintenance of RGCs to regulate the generation of upper layer neurons.

2021-06-29 | GSE179070 | GEO

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

The role of Insulinoma associated 1 protein in the development of the mammalian neocortex

Project description:Basal (intermediate) progenitors are the major source of neurons in the mammalian cerebral cortex. The molecular machinery governing basal progenitor biogenesis is unknown. Here we show that the zinc finger transcription factor Insm1 (insulinoma-associated 1) is expressed specifically in progenitors undergoing neurogenic divisions and has a key role in basal progenitor formation. Mouse embryos lacking Insm1 contained half the number of basal progenitors and showed a marked reduction in cortical plate radial thickness. Forced premature expression of Insm1 in neuroepithelial cells resulted in their mitosis occurring at the basal (rather than apical) side of the ventricular zone and induced expression of the basal progenitor marker Tbr2. Remarkably, these cells remained negative for Tis21, a marker of neurogenic progenitors, and did not generate neurons but underwent self-amplification. Our data imply that Insm1 is involved in the generation and expansion of basal progenitors, a hallmark of cerebral cortex evolution. Keywords: knock out, genetic modification,

2008-10-14 | GSE12294 | GEO

Transcription profiling of secondary neural stem cells from cortex and spinal cord reveals gene expression patterns consistent with regional derivation in culture

Project description:Neural stem cells (NSCs) can be isolated from different regions of the central nervous system. There has been controversy whether regional differences amongst stem and progenitor cells are cell intrinsic and whether these differences are maintained during expansion in culture. The identification of inherent regional differences has important implications for the use of these cells in neural repair. Here, we compared neural stem cells derived from the spinal cord and embryonic cortex. We found that while cultured cortical and spinal cord derived neural stem cells respond similarly to mitogens and are equally neuronogenic, they retain and maintain through multiple passages gene expression patterns indicative of the region from which they were isolated. Further microarray analysis identified 229 genes that were differentially expressed between cortical and spinal cord derived neurospheres. Experiment Overall Design: Cortex and and spinal cords were isolated from embryonic day 14 cd1 mice and cultured ad neurospheres for 2 passages in EGF and bFGF. 3 independent sets of cultures serve as biological replicates with a dye flip control for each hybridization, for a total of 6 arrays.

2009-02-20 | E-GEOD-9433 | biostudies-arrayexpress

Genome wide mRNA sequencing of induced pluripotent stem cell (iPSC) diffrentiated neural stem cells (NSCs).

Project description:The NSC differentiation of six validated iPSC lines were induced using commercially available PSC neural induction medium and following manufacturer method with minor modifications (Gibco). An extensive characterization of generated NSCs on day 14 (at passage P1) was performed using immunocytochemistry (ICC) analysis of the NSC specific markers and by genome wide mRNA sequencing. The iPSC differentiated NSCs expressed NSC specific markers Nestin, PAX6, SOX1 and SOX2 across all six samples. The average correlation coefficient at 95% CI between 6 NSC samples, calculated based on all expressed mRNAs, was 0.97 ± 0.008 suggesting a uniform differentiation of generated NSC lines. The generated NSC showed high expression of neuroepithelial genes/transcription factors (NES, SOX2, SOX1, PAX6, NOTCH1, MSI1,and CHD2) and genes/transcription factors of dorsal tube neuroepithelium (PAX3, GDF7, SOX9 and SNAI2) but lacked the expression of ventral tube neuroepithelial markers (NKX2-2, FOXA2 and SHH) suggesting a dorsal tube neuroepithelial transcriptomic and functional profile of the generated NSCs. A differential gene expression analysis of iPSC’s and NSC’s expressed transcription identified 4,033 mRNAs that were significantly differentially expressed (DE) between iPSCs and differentiated NSCs. The 2,006 DE mRNA were significantly upregulated in differentiated NSCs and were highly enriched in developmental functional categories such as embryonic development (572 mRNAs; FDR adjusted p-value range: 1.92x10-53 – 3.26x10-9), organism development (749 mRNAs; FDR adjusted p-value range: 1.92x10-53 – 4.30x10-9), nervous system development and function (629 mRNAs; FDR adjusted p-value range: 3.23x10-48 – 4.15x10-9), tissue development (655 mRNAs; FDR adjusted p-value range: 3.63x10-40 – 4.32x10-9) and organ development (406 mRNAs; FDR adjusted p-value range: 8.74x10-40 – 2.37x10-9).

2020-08-22 | GSE156617 | GEO

Individual Human Cortical Progenitors Can Produce Excitatory and Inhibitory Neurons

Project description:The cerebral cortex is a cellularly-complex structure comprised of a rich diversity of neuronal and glial cell types. Cortical neurons can be broadly categorized into two classes—glutamatergic excitatory neurons and GABAergic inhibitory interneurons. Previous developmental studies in rodents have led to the prevailing model that while excitatory neurons are born from progenitors located in the cortex, cortical interneurons are born from a separate population of progenitors located outside of the developing cortex in the ganglionic eminences1-5. However, the developmental potential of human cortical progenitors has not been thoroughly explored. Here we show that in addition to excitatory neurons and glia, human cortical progenitors are also capable of producing GABAergic neurons with the transcriptional characteristics and morphologies of cortical interneurons. By developing a cellular barcoding tool called “ScRNAseq-compatible Tracer for Identifying Clonal Relationships” (STICR), we were able to perform clonal lineage tracing of 1912 primary human cortical progenitors from six specimens and capture both the transcriptional identities and clonal relationships of their resulting progeny. A subpopulation of cortically-born GABAergic neurons were transcriptionally similar to cortical interneurons born from the caudal ganglionic eminence and these cells were frequently related to excitatory neurons and glia. Thus, our results demonstrate that individual human cortical progenitors can generate both excitatory neurons and cortical interneurons, providing a new framework for understanding the origins of neuronal diversity in the human cortex.

2021-11-06 | GSE187875 | GEO

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