Glucose and Oxygen Metabolism Coordinate Human Cortical Developmental Decisions

Area of Science:

• Neuroscience
• Developmental Biology
• Metabolic Regulation

Background:

• Understanding metabolic regulation is key for addressing neurodevelopmental disorders.
• Current in vitro models often use supraphysiologic nutrient and oxygen levels, limiting relevance to human brain development.

Purpose of the Study:

• To investigate how endogenous-like nutrient concentrations impact the metabolic state and developmental trajectory of human cortical cell types.
• To elucidate the role of specific metabolic pathways, like glycolysis and oxidative phosphorylation, in neurogenesis and cell fate determination.

Main Methods:

• Utilized human brain organoids to study cortical cell development under physiologically relevant glucose and oxygen conditions.
• Employed metabolomic and transcriptomic analyses to assess metabolic states and gene expression.
• Performed functional assays, including glycolysis inhibition, to determine the impact on cell differentiation and progenitor expansion.

Main Results:

• Physiologic glucose levels increased TCA cycle metabolites and oxidative phosphorylation gene expression, promoting expansion of cortical stem cells and upper-layer neurons.
• Oxygen levels had specific molecular effects, influencing deep-layer excitatory neuron development.
• Lactate signaling was found to suppress outer radial glia development and promote neurogenic progenitor self-renewal.

Conclusions:

• Metabolic regulation, particularly shifts in glucose reliance and oxygen utilization, plays a critical, cell-type-specific role in human neurodevelopment.
• Transitioning from stem cell self-renewal to progenitor diversification requires refined metabolic switches, including a shift from anaerobic to aerobic metabolism.
• Lactate signaling acts as a key regulator in suppressing differentiation and promoting self-renewal of specific progenitor populations.