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Metabolic Atlas of Early Human Cortex Identifies Regulators of Cell Fate Transitions

ABSTRACT: Cortical development involves rapid progenitor expansion and cell diversification that is likely supported by tightly regulated metabolic programs, yet these programs, particularly in human development remain largely uncharacterized. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. Across developmental stages, we observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis and pentose phosphate pathway (PPP) activity during late neurogenesis. Manipulation of glucose availability in cortical organoids altered progenitor and neuronal composition, increasing outer radial glia and inhibitory neurons populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes and promoted radial glial maturation. Ribose was sufficient to rescue the radial glia gene expression changes, revert organoid cell type composition, and restore the levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating radial glia cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE292425 | GEO | 2026/03/01

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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Metabolic Atlas of Early Human Cortex Identifies Regulators of Cell Fate Transitions

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