Regulation of Glycolysis by Pdk Functions as a Metabolic Checkpoint for Cell Cycle Quiescence in Hematopoietic Stem Cells

SummaryDefining the metabolic programs that underlie stem cell maintenance will be essential for developing strategies to manipulate stem cell capacity. Mammalian hematopoietic stem cells (HSCs) maintain cell cycle quiescence in a hypoxic microenvironment. It has been proposed that HSCs exhibit a distinct metabolic phenotype under these conditions. Here we directly investigated this idea using metabolomic analysis and found that HSCs generate adenosine-5′-triphosphate by anaerobic glycolysis through a pyruvate dehydrogenase kinase (Pdk)-dependent mechanism. Elevated Pdk expression leads to active suppression of the influx of glycolytic metabolites into mitochondria. Pdk overexpression in glycolysis-defective HSCs restored glycolysis, cell cycle quiescence, and stem cell capacity, while loss of both Pdk2 and Pdk4 attenuated HSC quiescence, glycolysis, and transplantation capacity. Moreover, treatment of HSCs with a Pdk mimetic promoted their survival and transplantation capacity. Thus, glycolytic metabolic status governed by Pdk acts as a cell cycle checkpoint that modulates HSC quiescence and function.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (243 K)Download as PowerPoint slideHighlights► LT-HSCs activate glycolysis and generate ATP in a HIF-1α-dependent manner ► Pdk overexpression in HIF-1αΔ/Δ HSCs restored glycolysis and stem cell capacity ► Pdk2−/−: Pdk4−/− LT-HSCs show defective glycolysis and cell cycle quiescence ► Pdk mimetic promotes the survival and transplantation capacity of LT-HSCs