Metabolic pathways that mediate expansion and homeostasis of hematopoietic lineages

Abstract

Abstract Due to the rarity of hematopoietic stem cells, their differentiation into progenitors then on to mature cells must occur with proliferation, leading to an expansion of each downstream population. This process, called transit amplification, is required to produce a sufficient mature cell population and must be balanced with survival to maintain homeostasis and prevent hematological malignancies. How transit amplification and subsequent homeostasis is controlled is not well understood but may involve metabolic switches. Various groups have demonstrated that hematopoietic expansion requires a switch from glycolysis to oxidative phosphorylation, but what induces this switch and the specific carbon sources that fuel it remain unclear. To address these questions, we employed mice conditionally deficient in mitochondrial pyruvate import, fatty acid oxidation, or glutamine hydrolysis and examined the requirements of these pathways in hematopoietic homeostasis. Ablation of carnitine palmitoyltransferase II (Cpt2) or glutaminase (Gls) had no effect on lineages examined, suggesting fatty acid oxidation and glutaminolysis are not required for the production or survival of various immune cells. In contrast, upon deletion of mitochondrial pyruvate carrier 2 (Mpc2), peripheral myeloid cell numbers declined dramatically. Over time after Mpc2 ablation, a recovery of myeloid cells was observed. This recovery was associated with increased proliferation of Mpc2-deficient progenitors relative to wild type counterparts immediately following genetic deletion. Further studies are being done to elucidate what metabolic pathway may allow myeloid progenitors to rapidly proliferate and recover after mitochondrial pyruvate ablation.