Glucose and Glutamine Metabolism Regulate Human Hematopoietic Stem Cell Lineage Specification

Abstract

The metabolic state of quiescent hematopoietic stem cells (HSCs) is an important regulator of self-renewal, but it is unclear whether or how metabolic parameters contribute to HSC lineage specification and commitment. Here, we show that the commitment of human and murine HSCs to the erythroid lineage is dependent upon glutamine metabolism. HSCs require the ASCT2 glutamine transporter and active glutamine metabolism for erythroid specification. Blocking this pathway diverts EPO-stimulated HSCs to differentiate into myelomonocytic fates, altering in vivo HSC responses and erythroid commitment under stress conditions such as hemolytic anemia. Mechanistically, erythroid specification of HSCs requires glutamine-dependent de novo nucleotide biosynthesis. Exogenous nucleosides rescue erythroid commitment of human HSCs under conditions of limited glutamine catabolism, and glucose-stimulated nucleotide biosynthesis further enhances erythroid specification. Thus, the availability of glutamine and glucose to provide fuel for nucleotide biosynthesis regulates HSC lineage commitment under conditions of metabolic stress.

Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE −/− Mice

“…33 However, these observations do not prove causality. Intriguingly, inhibition of glucose uptake with a 2-deoxyglucose (2-DG) analog has recently ben shown to inhibit myelopoiesis in human HSCs, 26 but the relevance to atherosclerosis has not been tested. The present study clearly establishes that the increased Glut1-dependent glucose utilization in the ApoE −/− HSPCs could divert these cells to a myelomonocytic fate leading to extramedullary myelopoiesis and subsequent macrophage deposition-dependent atherosclerotic plaque formation.…”

“…21,25 More recently, Oburoglu et al, have also reported that glucose utilization can dictate the myeloid lineage commitment in human HSCs. 26 Intriguingly, increased hematopoietic metabolic activity can be visualized by non-invasive PET-CT imaging with 18 FDG, a glucose analog, not only in inflamed atherosclerotic plaques, 27–30 but also in the spleen of patients with cardiovascular diseases, 31,32 reflecting most likely an extramedullary hematopoiesis. 33 However, the relevance of these observations as well as the underlying mechanisms are not fully understood.…”

Metabolic traits of cancer stem cells

“…Knockdown of ASCT2 decreased glutamine uptake and inhibited erythroid differentiation. Additionally, the authors demonstrated that the commitment to an erythroid state was not restored by solely feeding the TCA cycle with cell-permeable αKG, but rather it depended on nucleotides produced by glutamine metabolism (Oburoglu et al, 2014). …”

Mechanisms linking mtDNA damage and aging

“…It is still unclear whether mtDNA damage directly reduces the somatic stem cell pool or only their renewal capacities, and if mitochondrial impairment occurs intrinsically in the stem cells or indirectly owing to a systemic effect. Stem cells contain, in general, fewer mitochondria, as their quiescent state requires less energy and relies more on glycolysis than oxidative metabolism [128, 129]. Therefore, it is possible that their sensitivity to the same amount of mtDNA damage is increased compared to differentiated cells that contain a larger amount of mitochondria.…”