title: 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.
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Leal
authors: L
authors: Oburoglu
authors: Cancer Research UK, Beatson Institute, Glasgow, G61 1BD, UK.
authors: Saverio
authors: S
authors: Tardito
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Vanessa
authors: V
authors: Fritz
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Stéphanie C
authors: SC
authors: de Barros
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Peggy
authors: P
authors: Merida
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Marco
authors: M
authors: Craveiro
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: João
authors: J
authors: Mamede
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Gaspard
authors: G
authors: Cretenet
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Cédric
authors: C
authors: Mongellaz
authors: New York Blood Center, New York, NY 10032, USA; Department of Bioengineering, Zhengzhou University, Zhengzhou 450051, China.
authors: Xiuli
authors: X
authors: An
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Dorota
authors: D
authors: Klysz
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Jawida
authors: J
authors: Touhami
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France.
authors: Myriam
authors: M
authors: Boyer-Clavel
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Jean-Luc
authors: JL
authors: Battini
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Valérie
authors: V
authors: Dardalhon
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Valérie S
authors: VS
authors: Zimmermann
authors: New York Blood Center, New York, NY 10032, USA.
authors: Narla
authors: N
authors: Mohandas
authors: Cancer Research UK, Beatson Institute, Glasgow, G61 1BD, UK.
authors: Eyal
authors: E
authors: Gottlieb
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France.
authors: Marc
authors: M
authors: Sitbon
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France. Electronic address: kinet@igmm.cnrs.fr.
authors: Sandrina
authors: S
authors: Kinet
authors: Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique UMR5535, Universités de Montpellier 1 et 2, F-34293 Montpellier, France; Laboratory of Excellence GR-Ex, Paris 75015, France. Electronic address: taylor@igmm.cnrs.fr.
authors: Naomi
authors: N
authors: Taylor
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D026962:Amino Acid Transport System ASC / Q000378:metabolism*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001692:Biological Transport; D002454:Cell Differentiation; D019070:Cell Lineage; D002853:Chromatography, Liquid; D004912:Erythrocytes / Q000166:cytology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D026962:Amino Acid Transport System ASC; D018952:Antigens, CD34; D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; C420506:SLC1A5 protein, human; C498850:Slc1a5 protein, mouse; D005973:Glutamine; D049452:Green Fluorescent Proteins; D051997:ADP-ribosyl Cyclase 1; D005947:Glucose