ABSTRACT
As human pluripotent stem cells (hPSCs) exit pluripotency, they reportedly switch from glycolytic energy production to primarily mitochondrial metabolism. Here, we show that upon ectoderm differentiation to neural precursor cells (NPCs), hPSCs increase glycolytic rate, ultimately producing more carbon as lactate than is consumed as glucose. However, glucose, lactate and pyruvate utilization decrease to half their PSC levels by the NPC stage, establishing a more quiescent metabolic state. Furthermore, we characterize a metabolic exit event within the first 24 h of differentiation, plausibly necessary to transition hPSCs out of the pluripotent state. Contrary to current thinking, mitochondrial mass does not increase during NPC induction. Instead, mitochondrial DNA copies and mitochondrial activity decrease, suggesting that mitochondrial metabolism either requires suppression, or is not required, for nascent ectoderm differentiation. Our work, therefore, contrasts with the dogma that the hPSC state is primarily glycolytic, transitioning to an oxidative metabolism upon the loss of the pluripotent state. Instead, we show that heightened glycolytic metabolism is acquired, indicating that metabolic modulation of both glycolysis and mitochondrial metabolism occurs during exit from pluripotency in hPSCs.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: J.G.L., A.J.H., D.K.G.; Methodology: J.G.L., A.J.H.; Software: J.G.L.; Validation: J.G.L.; Formal analysis: J.G.L.; Investigation: J.G.L.; Resources: D.K.G.; Data curation: D.K.G.; Writing - original draft: J.G.L.; Writing - review & editing: J.G.L., A.J.H., D.K.G.; Visualization: A.J.H., D.K.G.; Supervision: A.J.H., D.K.G.; Project administration: A.J.H., D.K.G.; Funding acquisition: A.J.H., D.K.G.
Funding
This work was supported by the Australian Research Council Special Research Initiative Stem Cells Australia (SR110001002), and a Jasper Loftus-Hills Award (UTR7.116), an Alfred Nicholas Fellowship Award (UTR6.197), and an F. H. Drummond Travel Award (UTR6.184) from the University of Melbourne.
Supplementary information
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.168997.supplemental
- Received June 14, 2018.
- Accepted September 18, 2018.
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