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Generation of human cerebral organoids with a structured outer subventricular zone

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224346 | GEO | 2024/04/15

REPOSITORIES: GEO

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Gene expression profile at single cell level of human cerebral cortical organoids with and without LIF treatment

Project description:Proper regulation of the proliferation and differentiation of radial glia (RG), the neural stem cells of the developing cortex, is fundamental for brain growth and organization. In humans, a specialized RG subtype, the outer radial glia (oRG), are abundant and give rise to diverse neuronal and glial progeny. However, the mechanisms regulating oRG development and differentiation are not fully understood. Here we investigated the regulation of oRG expansion and lineage potential by perturbing Leukemia Inhibitory Factor (LIF) signaling in the developing human cortex and in human pluripotent stem cell (PSC)-derived cortical organoids. LIF receptors are specifically expressed in oRG cells during neurogenesis, and, consistent with the previously described role of this cytokine as an activator of stem cell self-renewal, LIF treatment increased the number of oRG cells. Surprisingly, LIF treatment also increased the production of inhibitory interneurons (INs) in the cortex. Comparative transcriptomic analysis suggested that these INs resemble INs produced in the caudal ganglionic eminence (CGE). To test if oRG cells are the progenitors of these CGE-like INs, we isolated oRG cells from primary developing cortex and cultured them for several weeks with and without LIF treatment. We found that CGE-like INs were produced by oRG cells, and their abundance is increased by LIF treatment. Together, these observations suggest that LIF signaling regulates oRG lineage potential and capacity to generate CGE-like INs.

2023-03-23 | GSE227640 | GEO

A restricted period for formation of Outer Subventricular Zone defined by Cdh1 and Trnp1 levels

Project description:The Outer Subventricular Zone (OSVZ) is a germinal layer playing key roles in the development of the neocortex, with particular relevance in gyrencephalic species like human and ferret where it contains abundant basal Radial Glia Cells (bRGCs) that promote cortical expansion. Here we identify a brief period in ferret embryonic development when apical RGCs generate a burst of bRGCs that become founders of the OSVZ. After this period, bRGCs in the OSVZ proliferate and self-renew exclusively locally, thereby forming a self-sustained lineage independent from the other germinal layers. The time window for the brief period of OSVZ bRGC production is delineated by the coincident down-regulation of Cdh1 and Trnp1, and their up-regulation reduces bRGC production and prevents OSVZ seeding. This mechanism in cortical development may have key relevance in brain evolution and disease Samples were analyzed with 3 replicates of each of them (except E34SVZ that has 2 replicantes). Comparisons were done taking different reference sample depending on the comparison.

2016-06-01 | E-GEOD-63203 | biostudies-arrayexpress

A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding

Project description:The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, mainly results from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lisencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion; that oRGs are necessary for neocortical folding; and that defects in oRG expansion may cause primary microcephaly.

2022-08-31 | GSE211990 | GEO

A restricted period for formation of Outer Subventricular Zone defined by Cdh1 and Trnp1 levels

2016-06-01 | GSE63203 | GEO

Enhanced cortical neural stem cell identity through short SMAD/WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells.

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2022-03-16 | GSE189981 | GEO

Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal.

Project description:The expansion of the neocortex during mammalian brain evolution results primarily from an increase in neural progenitor cell divisions in its two principal germinal zones during development, the ventricular zone (VZ) and the subventricular zone (SVZ). Using mRNA sequencing, we analyzed the transcriptomes of fetal human and embryonic mouse VZ, SVZ and cortical plate (CP). We describe sets of genes that are up- or down-regulated in each germinal zone. These data suggest that cell adhesion and cell-extracellular matrix (ECM) interactions promote the proliferation and self-renewal of neural progenitors in the developing human neocortex. Notably, relevant ECM-associated genes include distinct sets of collagens, laminins, proteoglycans and integrins, along with specific sets of growth factors and morphogens. Our data establish a basis for identifying novel cell-type markers and open up avenues to unravel the molecular basis of neocortex expansion during evolution. Total RNA was isolated from the VZ, inner SVZ (ISVZ), outer SVZ (OSVZ) and CP of six 13-16 weeks post-conception (w.p.c.) human fetuses and from the VZ, SVZ and CP of five E14.5 mouse embryos using laser capture microdissection of Nissl-stained cryosections of dorsolateral telencephalon. Poly A+ RNA was used as template for the preparation of cDNA which were then subjected to single-end 76-bp RNA-Seq.

2012-07-02 | E-GEOD-38805 | biostudies-arrayexpress

A novel population of Hopx-dependent human-like basal radial glial cells in the developing mouse neocortex

Project description:A specific subpopulation of neural progenitor cells, the basal radial glia cells (bRGCs) of the outer subventricular zone (OSVZ), are thought to have a key role in the evolutionary expansion of mammalian neocortex. In the developing lissencephalic mouse neocortex, bRGCs exist at low abundance and show significant molecular differences from bRGCs in developing gyrencephalic species. Here, we demonstrate that developing mouse medial neocortex, in contrast to the canonically studied lateral neocortex, exhibits an OSVZ and an abundance of bRGCs similar to that in developing gyrencephalic neocortex. Unlike bRGCs in developing mouse lateral neocortex, the bRGCs in medial neocortex exhibit human bRGC-like gene expression, including expression of Hopx, a human bRGC marker. Disruption of Hopx expression in mouse embryonic medial neocortex and forced Hopx expression in mouse embryonic lateral neocortex demonstrate that Hopx is required and sufficient, respectively, for a bRGC abundance as found in developing gyrencephalic neocortex. Taken together, our data identify a novel bRGC subpopulation in developing mouse medial neocortex that is highly related to bRGCs of developing gyrencephalic neocortex.

2018-10-10 | GSE120976 | GEO

A novel population of Hopx-dependent basal radial glial cells in the developing mouse neocortex

Project description:A specific subpopulation of neural progenitor cells, the basal radial glial cells (bRGCs) of the outer subventricular zone (OSVZ), are thought to have a key role in the evolutionary expansion of the mammalian neocortex. In the developing lissencephalic mouse neocortex, bRGCs exist at low abundance and show significant molecular differences from bRGCs in developing gyrencephalic species. Here, we demonstrate that the developing mouse medial neocortex (medNcx), in contrast to the canonically studied lateral neocortex (latNcx), exhibits an OSVZ and an abundance of bRGCs similar to that in developing gyrencephalic neocortex. Unlike bRGCs in developing mouse latNcx, the bRGCs in medNcx exhibit human bRGC-like gene expression, including expression of Hopx, a human bRGC marker. Disruption of Hopx expression in mouse embryonic medNcx and forced Hopx expression in mouse embryonic latNcx demonstrate that Hopx is required and sufficient, respectively, for a bRGC abundance as found in developing gyrencephalic neocortex. Taken together, our data identify a novel bRGC subpopulation in developing mouse medNcx that is highly related to bRGCs of developing gyrencephalic neocortex.

2018-10-10 | GSE121008 | GEO

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

Single Cell Analysis Reveals Unexpected Transcriptional Heterogeneity of Neural Progenitors in the Developing Human Cortex

Project description:The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans, but virtually absent in rodents, called â??outer radial gliaâ?? (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined cell type-specific sorting with transcriptome-wide RNA-sequencing to identify genes enriched in human ORG, including targets of the transcription factor Neurogenin, and previously uncharacterized, evolutionarily dynamic, long noncoding RNAs. Single-cell transcriptional profiling of human, ferret, and mouse progenitors showed that more human RGC co-express proneural Neurogenin targets than in ferret or mouse, suggesting greater self-renewal of neuronal lineage-committed progenitors in humans. Finally, we show that activating the Neurogenin pathway in ferret RGC promotes delamination and outward migration. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors. Three biological replicates of human late mid-fetal cortex (18 to 19 weeks of gestation) were dissociated and immunolabeled. Apical and outer radial glial cells were purified by FACS and compared to an immunonegative population, predominantly neurons.

2015-02-24 | E-GEOD-66217 | biostudies-arrayexpress

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