Bioenergetic Changes Underline Plasticity of Murine Embryonic Stem Cells

Area of Science:

• Stem cell biology
• Cellular metabolism
• Developmental biology

Background:

• Murine embryonic stem cells (mESCs) exhibit a time-dependent plasticity window during early differentiation.
• Loss of leukemia inhibitory factor (LIF) for 48 hours leads to irreversible differentiation, unlike a 24-hour deprivation.
• Understanding the bioenergetic profiles associated with mESC plasticity is crucial.

Purpose of the Study:

• To investigate the bioenergetic profiles of pluripotent and committed mESC states.
• To identify specific metabolic changes linked to mESC plasticity.
• To elucidate the role of energy metabolism in the loss of pluripotency.

Main Methods:

• Multiparametric bioenergetic analysis of mESCs under varying LIF conditions.
• Assessment of cellular energy reliance on oxidative phosphorylation (OXPHOS) and glycolysis.
• Analysis of gene expression, differentiation capacity, and mitochondrial morphology.

Main Results:

• Pluripotent and reversibly committed mESCs show metabolic flexibility, utilizing both OXPHOS and glycolysis.
• Inhibition of glycolysis or OXPHOS did not significantly alter pluripotency gene expression or differentiation capacity.
• Irreversible differentiation correlated with altered mitochondrial morphology, increased glycolysis-derived ATP, and reduced mitochondrial activity.

Conclusions:

• mESC plasticity is associated with a bivalent metabolic state, allowing shifts between glycolysis and OXPHOS.
• LIF removal induces a glycolytic shift, leading to the loss of the ability to revert to a pluripotent state.
• Metabolic reprogramming is a key factor in the time-dependent loss of mESC plasticity.