Aerobic glycolysis, characterized by pyruvate reduction to lactate, serves proliferation in cancer cells and stem cells. To clarify whether this metabolic profile is universal to epithelial stem cells, despite vast differences in physiological turnover rates, we characterized the metabolic phenotype of bipotent liver progenitors (low turnover) relative to intestinal progenitors (high turnover). Using human liver and intestinal organoids, we show high glycolytic fluxes which provide substrates for cellular building blocks and reducing equivalents in proliferating progenitors, compared to their quiescent differentiating counterparts. Similar to cancer and pluripotent stem cells, intestinal progenitors display aerobic glycolysis with pyruvate reduction to lactate to serve their high proliferative demands. Strikingly, liver progenitors combine high glycolysis with substantial mitochondrial oxidation of pyruvate, which they require for both proliferation and maintenance of stemness. This concurs with the anabolic and epigenetic effects of mitochondrial pyruvate oxidation and the homeostatic liver function with low physiological turnover rates.
Schene, Imre Firmin and Ramos, Rúben J. and van Vugt, Anke H.M. and Truong, Hoa and van den Heuvel, Dave J. and Gerritsen, Hans C. and Houtkooper, Riekelt H. and van Weeghel, Michel and Middendorp, Sabine and Mokry, Michal and Spee, Bart and Schneeberger, Kerstin and Nikkels, Peter G.J. and Huch, Meritxell and Clevers, Hans and Nieuwenhuis, Edward E.S. and van Hasselt, Peter M. and Fuchs, Sabine A., Bipotent Liver Progenitors Depend on Glycolysis and Mitochondrial Pyruvate Oxidation for Stem Cell Functions. Available at SSRN: https://ssrn.com/abstract=3564994 or http://dx.doi.org/10.2139/ssrn.3564994
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