Distinct roles of the preparatory and payoff phases of glycolysis in hematopoietic stem cells

In physiological conditions, most adult hematopoietic stem cells (HSCs) maintain a quiescent state. Glycoly-sis is a metabolic process that can be divided into preparatory and payoff phases. Although the payoff phase maintains HSC function and properties, the role of the preparatory phase remains unknown. In this study, we aimed to investigate whether the preparatory or payoff phases of glycolysis were required for maintenance of quiescent and proliferative HSCs. We used glucose-6-phosphate isomerase (Gpi1) as a rep-resentative gene for the preparatory phase and glyceraldehyde-3-phosphate dehydrogenase (Gapdh) as a representative gene for the payoff phase of glycolysis. First, we identified that stem cell function and survival were impaired in Gapdh-edited proliferative HSCs. Contrastingly, cell survival was maintained in quiescent Gapdh-and Gpi1-edited HSCs. Gapdh-and Gpi1-defective quiescent HSCs maintained adenosine-triphos-phate (ATP) levels by increasing mitochondrial oxidative phosphorylation (OXPHOS), whereas ATP levels were decreased in Gapdh-edited proliferative HSCs. Interestingly, Gpi1-edited proliferative HSCs main-tained ATP levels independent of increased OXPHOS. Oxythiamine, a transketolase inhibitor, impaired pro-liferation of Gpi1-edited HSCs, suggesting that the nonoxidative pentose phosphate pathway (PPP) is an alternative means to maintain glycolytic flux in Gpi1-defective HSCs. Our findings suggest that OXPHOS compensated for glycolytic deficiencies in quiescent HSCs, and that in proliferative HSCs, nonoxidative PPP compensated for defects in the preparatory phase of glycolysis but not for defects in the payoff phase. These findings provide new insights into regulation of HSC metabolism, which could have implications for development of novel therapies for hematologic disorders.& COPY; 2023 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Automated summary

In physiological conditions, most adult hematopoietic stem cells (HSCs) maintain a quiescent state. The role of the preparatory phase of glycolysis in maintaining HSCs is unknown. However, in this study, it was found that the payoff phase is vital for HSC function, while the preparatory phase is essential for HSC survival. These findings reveal new insights into HSC metabolism regulation and could contribute to the development of novel therapies for hematologic disorders.