1. Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification.
- Author
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Oburoglu L, Tardito S, Fritz V, de Barros SC, Merida P, Craveiro M, Mamede J, Cretenet G, Mongellaz C, An X, Klysz D, Touhami J, Boyer-Clavel M, Battini JL, Dardalhon V, Zimmermann VS, Mohandas N, Gottlieb E, Sitbon M, Kinet S, and Taylor N
- Subjects
- ADP-ribosyl Cyclase 1 metabolism, Animals, Antigens, CD34 metabolism, Biological Transport, Cell Differentiation, Chromatography, Liquid, Erythrocytes cytology, Glycolysis, Green Fluorescent Proteins metabolism, Humans, Mass Spectrometry, Mice, Mice, Inbred C57BL, Minor Histocompatibility Antigens, RNA, Small Interfering metabolism, Amino Acid Transport System ASC metabolism, Cell Lineage, Gene Expression Regulation, Glucose metabolism, Glutamine metabolism, Hematopoietic Stem Cells cytology
- 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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