Glycolysis and the formation of building blocks in proliferating epithelial cells

Background: The Warburg effect (aerobic glycolysis) is a well-known hallmark of proliferating cancer cells. Recently, this glycolytic phenotype was
detected in some healthy proliferating cell types, but the function remains
controversial. Despite their importance in cancer development and prospects
for regenerative strategies for metabolic disorders, little is known about the
metabolic phenotype in epithelial adult stem cells.
Methods: We applied expression profiling and functional metabolic analyses
to liver and intestinal organoids to unravel the metabolic configuration of
proliferating and differentiating epithelial stem cells under controllable
conditions.
Results: We show that proliferating epithelial adult stem cells display high
glycolytic transcription, activity and capacity but similar oxidative phosphorylation when compared to differentiated cells. We observed upregulation of the
pathways branching from glycolysis during proliferation, fueling generation of
building blocks needed for cell replication. During differentiation, the decrease
in expression of stem cell markers, regulators of proliferation and cell cycle markers were early events, preceding the drop in expression of glycolytic
enzymes. This suggests that glycolysis and the branching biosynthetic pathways respond to changing cellular biomass demand. Moreover, we observed
that proliferation requires glycolysis but inhibition of glycolysis does not induce differentiation.
Discussion: We provide the most comprehensive characterization of the metabolic configuration in proliferating and differentiated epithelial adult stem
cells to date. Through this work, we reveal a crucial role for glycolysis in the
production of cellular building blocks in proliferative epithelial stem cells to
meet biomass demands. This might well represent the optimal metabolic configuration for any highly proliferative cell in physiology and malignancy.