The role of glycolysis in human cerebral cortex development using in vitro and in vivo PSC models

Cellular metabolism is essential for tissue formation, energy production, and systemic homeostasis and becomes dysregulated in many disease states. Glucose metabolism dysregulation is a common phenotype across human neurodevelopmental disorders. In the context of human cerebral cortex development, there’s a limited understanding of how metabolic pathways, such as glycolysis, impact the proliferation and differentiation of cortical cells. The technical challenges of studying primary in vivo cortical tissue at a cellular and molecular level led to the development of human pluripotent stem cell (PSC) derived cortical organoids. Cortical organoids are a highly tractable model system that can be used for high-throughput investigation of early stages of development and corresponding glycolytic programs. Through transplantation of cortical organoids into the developing mouse cortex, human cortical cells can also be studied in an in vivo environment that more closely resembles endogenous development where the impact of metabolism in typical developmental programs and disease states can be studied. While current data is preliminary, initial observations suggest that cortical populations increase glucose uptake over time and regulation of glucose uptake rates occur in cell type-specific manner. Additionally, mouse transplantation data suggests that glycolytic activity is downregulated post-transplantation, suggesting that the in vitro environment contributes to metabolic state. The more dynamic range of metabolic states in vivo may impact the rate of differentiation and maturation in cellular populations in the transplant model. I hypothesize that the more endogenous-like regulation of glycolysis may impact the proliferative window and expansion of key progenitor cell types in the human brain, particularly the intermediate progenitor cells. Prolonged expansion of intermediate progenitor populations throughout development is responsible for the large number of neurons in the mature human cortex, which contributes to overall function and complexity. Glucose metabolism dynamics may influence early cortical development programs which suggests changes in glucose metabolism may contribute to the onset of neurodevelopmental disorders.