Human induced pluripotent stem cells (iPSCs) offer significant potential to investigate human development, etiology of complex disease using patient cells, and as regenerative therapeutics for personalized medicine strategies. We leverage patient-derived iPSCs and complex 3D tissue-like cell culture models, called organoids, to investigate molecular regulators of brain development and dysregulation in neurological disease states. Due to neurological disorder relevance, we are focusing on the role of metabolism in the developmental trajectory of the human brain. The human cerebral cortex has immense metabolic demands due to increasingly specialized cell types that differentiate during tissue formation, which ultimately regulate neurological function. However, the role of metabolism in developmental programs regulating appropriate cell expansion, fate, and organization remains an outstanding question. Using multi-omic and orthogonal functional approaches, we are interrogating the regulatory role of metabolic pathway activity in human neurodevelopmental decisions. Moving forward, we will co-opt gained understanding of nutrient accessibility and metabolic requirements to improve the fidelity of human neural cell culture platforms for increasingly accurate neurological disease modeling.
