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

ABSTRACT: Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity under a variety of derivation methods, suggesting inadequate patterning of early neural stem cell (NSC) starting populations. Here we show that a short combined Dual SMAD/WNT inhibition course during early organoid establishment is sufficient for yielding robust and lasting cortical identity with efficient suppression of non-cortical fates in organoid NSCs. In contrast, other widely used methods are inconsistent in their cortical specification capacity. Furthermore, combined inhibition selectively enriches for outer radial glia (oRG) cells in organoids that demarcate well-defined outer sub-ventricular (oSVZ)-like regions. Finally, combined inhibition enables superior NSC radial organization, further facilitates the generation of molecularly distinct deep and upper cortical layer neurons, and uncovers cortex-specific microcephaly defects. Thus, combined inhibition is critical for establishing a rich cortical cell repertoire, for enabling fundamental cytoarchitectural features of cortical development, and for meaningful disease modeling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189981 | GEO | 2022/03/16

REPOSITORIES: GEO

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

Project description:Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early dual-SMAD/WNT inhibition course is necessary and sufficient for establishing robust and lasting cortical organoid NSC identity, efficiently suppressing of non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC specification capacity. Accordingly, this method selectively enriches for outer radial glia (oRG) NSCs, which cytoarchitecturally demarcate well-defined outer sub-ventricular (oSVZ)-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD/WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring fundamental molecular and cytoarchitectural features of cortical development and meaningful disease modeling.

| EGAS00001006063 | EGA

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

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

2016-06-01 | GSE63203 | GEO

scRNA-seq of ferret cortical germinal zones from splenial gyrus and lateral sulcus (Borrell lab)

Project description:Diversity of cortical radial glia cells (RGCs) and their complex relationships to generate neurons in species with expanded germinal zones and a folded cortex, remains unclear. We used single-cell RNA sequencing (scRNA-seq) of microdissected cortical germinal layers (ventricular zone (VZ) and outer subventricular zone (OSVZ)), from two cortical regions (splenial gyrus (SG) and neighboring lateral sulcus (LS)) at two critical time points for ferret cortex development (embryonic day (E) 34 and postnatal day (P) 1) to distinguish the molecular diversity of progenitors and newborn neurons, and study their transcriptomic trajectories.

2024-03-27 | GSE219254 | GEO

Single cell analysis of iPSC-derived cortical organoids in biofunctionalized gelatin hydrogels

2024-07-01 | E-MTAB-14203 | biostudies-arrayexpress

Generation of Brain Region-specific Organoids using a Miniaturized Spinning Bioreactor and Modelling ZIKV Exposure

Project description:Cerebral organoids, three-dimensional cultures that model organogenesis, provide a new platform to investigate human brain development. High cost, variability and tissue heterogeneity limit accessibility and broad applications of current organoid technologies. Here we developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs. These organoids recapitulate key features of human cortical development, including progenitor zone organization, neurogenesis, gene expression, and importantly, a distinct human-specific outer radial glia cell layer. We have also developed protocols to generate midbrain and hypothalamic organoids. Finally, we employed this forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed that preferential, productive ZIKA infection of cortical neural progenitors leads to increased cell death and reduced proliferation, resulting in decreased neuronal cell layer volume that resembles microcephaly. Together, our brain region-specific organoids and SpinΩ provide an accessible and versatile platform for modeling human brain development and diseases, and for compound testing.

2016-04-22 | GSE80073 | GEO

Novel primate miRNAs co-evolved with ancient target genes in germinal zone specific expression patterns [miRNA-Seq]

Project description:Major non primate-primate differences in corticogenesis include the dimensions, precursor lineages and developmental timing of the germinal zones (GZ). microRNAs (miRNAs) of laser dissected GZ compartments and cortical plate (CP) from embryonic E80 macaque visual cortex were deep sequenced. The CP and the GZ including Ventricular Zone (VZ), outer and inner subcompartments of the Outer SubVentricular Zone (OSVZ) in area 17 displayed unique miRNA profiles. miRNAs present in primate, but absent in rodent, contributed disproportionately to the differential expression between GZ sub-regions. Prominent among the validated targets of these miRNAs were cell-cycle and neurogenesis regulators. Co-evolution between the emergent miRNAs and their targets suggested that novel miRNAs became integrated into ancient gene circuitry to exert additional control over proliferation. We conclude that multiple cell-cycle regulatory events contribute to the emergence of primate-specific cortical features, including the OSVZ, generated enlarged supragranular layers, largely responsible for the increased primate cortex computational abilities. Seven brain regions (VZ17, OSVZ17int, OSVZ17ext, CP17, VZ18, OSVZ18, CP18). OSVZ17int corresponds to the inner (apical) third of OSVZ 17 and OSVZ17ext to the most outer (basal) third of OSVZ 17, located immediately below the Outer Fiber Layer (Smart et al., 2002; Betizeau et al., 2013)

2014-02-27 | E-GEOD-52606 | biostudies-arrayexpress

Single cell analysis of iPSC-derived cortical organoids in biofunctionalized gelatin hydrogels

Project description:Human neural organoid models have become an important tool for studying neurobiology. In this work, we compared Matrigel to an N-cadherin peptide-functionalized gelatin methacryloyl hydrogel (termed GelMA-Cad) for culturing cortical neural organoids. Specifically, we compare five materials: (1) Matrigel, (2) GelMA-Cad with high crosslinker (HC), (3) GelMA-Cad with low crosslinker (LC), (4) GelMA HC and (5) GelMA LC. We determined that both mechanical properties and peptide presentation can tune cell fate and diversity in gelatin-based matrices during differentiation. Of particular note, cortical organoids cultured in GelMA-Cad produce higher numbers of neurogenic and ciliated radial glia and upper-layer excitatory neurons—an important population for modeling neurodegenerative disease—compared to GelMA and Matrigel controls.

2024-02-28 | E-MTAB-13828 | biostudies-arrayexpress

Primate-specific gene TMEM14B promotes cortical expansion and folding

Project description:A massively expanded outer subventricular zone (OSVZ) in the primate and human has been proposed for generating majority of neocortical neurons, which consists of basally located radial glia cells. Previous studies with various strategies have tried to recognize genes specifically expressed in those cells; however, the molecular and cellular features of these cells still remain uncertain. By profiling gene expression across single cells isolated from cellular anatomy location and subtype sorting, we identified a primate-specific gene TMEM14B as a novel marker for basally located radial glia. Expression of TMEM14B induced dramatic increase in the number of radial glial and OSVZ region. Finally, we found that OSVZ progenitor’s extensive proliferative potential was up regulated through IQGAP1 phosphorylation and nuclear translocation, and remarkably, led to the gyrification in postnatal mouse. These results highlight that evolutionary expansion promoted by primate-specific genes enabling the evolutionary expansion and folding of the human neocortex.

2016-12-02 | GSE90734 | GEO

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