Oxygen Regulates Human Pluripotent Stem Cell Metabolic Flux

Area of Science:

• Cell Biology
• Metabolic Engineering
• Epigenetics

Background:

• Cell metabolism critically influences cell fate decisions in human pluripotent stem cells (hPSC).
• Most research on hPSC metabolism occurs at ambient oxygen (20%), not physiological oxygen levels (5%).

Purpose of the Study:

• To investigate the distinct effects of 5% and 20% oxygen on hPSC metabolism, epigenetics, and gene expression.
• To understand how oxygen tension shapes metabolic pathways and epigenetic landscapes in hPSCs.

Main Methods:

• Integrated analysis of metabolic, transcriptomic (RNA-seq), and epigenetic data.
• Utilized ¹³C-glucose labeling to trace metabolic flux.
• Assessed histone modifications (acetylation and trimethylation) and mitochondrial activity.

Main Results:

• 5% oxygen increased glycolytic intermediates, glycogen, antioxidant response, and H3K9/H3K27 acetylation, correlating with open chromatin.
• 20% oxygen enhanced TCA cycle flux, mitochondrial activity, ATP production, and cell cycle gene expression.
• Oxygen differentially regulated methyltransferase and demethylase activity, impacting the epigenetic landscape.

Conclusions:

• Oxygen tension is a key determinant of metabolic flux and carbon fate in hPSCs.
• Distinct oxygen levels induce unique metabolic profiles and epigenetic modifications, influencing hPSC behavior.
• Oxygen's influence on methyltransferase/demethylase activity and chromatin structure warrants further mechanistic investigation.