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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134216 | GEO | 2020/01/01

REPOSITORIES: GEO

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Project description:We sought to characterize cellular heterogeneity in the human cerebral cortex at a molecular level during cortical neurogenesis. We captured single cells and generated sequencing libraries using the C1TM Single-Cell Auto Prep System (Fluidigm), the SMARTer Ultra Low RNA Kit (Clontech), and the Nextera XT DNA Sample Preparation Kit (Illumina). We performed unbiased clustering of the single cells and further examined transcriptional variation among cell groups interpreted as radial glia. Within this population, the major sources of variation related to cell cycle progression and the stem cell niche from which radial glia were captured. We found that outer subventricular zone radial glia (oRG cells) preferentially express genes related to extracellular matrix formation, migration, and stemness, including TNC, PTPRZ1, FAM107A, HOPX, and LIFR and related this transcriptional state to the position, morphology, and cell behaviors previously used to classify the cell type. Our results suggest that oRG cells maintain the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby contributing to the developmental and evolutionary expansion of the human neocortex. For study version 2, we have updated this data set to include additional primary cells that we infer to represent microglia, endothelial cells, and immature astrocytes, as well as additional cells from the developing neural retina, and from iPS-cell derived cerebral organoids. The genes distinguishing these cell populations may reveal biological processes supporting the diverse functions of these cell types as well as vulnerabilities of specific cell types in human genetic diseases and in viral infections. For study version 3, we have updated the data set to include additional primary cells, including those published in Nowakowski, et al., Science 2017: "Spatiotemporal Gene Expression Trajectories Reveal Developmental Hierarchies of the Human Cortex" (in press)

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

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