Journal Article Ahead of print 2 citations
PubMed: 42551423 DOI: 10.1016/j.cell.2026.07.023
Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions.
Cell
Authors: Jessenya Mil, Jose A Soto, Abigail S Krall, Julia Peloggia, Sara Frigui, Olivia S Fong, Laila Sathe, Nedas Matulionis, Francesca Day, Linsey Stiles, Katrina P Montales, Daria J Azizad, Carlos E Gonzalez, Elisa Fazzari, Matthew X Li, Patricia R Nano, Antoni A Martija, Cesar A Perez-Ramirez, Claudia V Nguyen, Brittney Wick, Weihong Ge, Ryan L Kan, Madeline G Andrews, Maximilian Haeussler, Michael F Wells, Heather R Christofk, Aparna Bhaduri
Affiliations
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
- Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.
- School of Biological and Health Systems Engineering, Arizona State University, Phoenix, AZ, USA.
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Abstract
Cortical development involves rapid progenitor expansion and cell diversification supported by tightly regulated metabolic programs, yet these programs remain largely uncharacterized in human development. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. 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 cell-type composition, increasing outer radial glia (oRG) and inhibitory neuron populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes. Ribose was sufficient to rescue radial glia (RG) gene expression changes, revert organoid cell-type composition, and restore levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating RG cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.
MeSH
Cells, Genes, Neuroglia, Cell Biology, Organoids, Metabolomics, Pentoses, Neurodevelopment