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

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.