The Role of Glycolysis in Human Cerebral Cortex Development Using in vitro and in vivo Pluripotent Stem Cell Models

Cellular metabolism is an essential process required for tissue formation, energy production and systemic homeostasis and becomes dysregulated in many disease states. In the context of human cerebral cortex development, there’s a limited understanding of how metabolic pathways, such as glycolysis, impacts 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 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.