1. Glucose and Glutamine Metabolism Regulate Human Hematopoietic Stem Cell Lineage Specification
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Narla Mohandas, Dorota Klysz, Jawida Touhami, Marco Craveiro, João I. Mamede, Saverio Tardito, Sandrina Kinet, Stéphanie C. De Barros, Jean-Luc Battini, Xiuli An, Cédric Mongellaz, Naomi Taylor, Eyal Gottlieb, Peggy Merida, Vanessa Fritz, Marc Sitbon, Myriam Boyer-Clavel, Valérie S. Zimmermann, Leal Oburoglu, Gaspard Cretenet, Valérie Dardalhon, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Cancer Research UK Beatson Institute [Glasgow], New York Blood Center, Zhengzhou University, BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
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Regulation of gene expression ,0303 health sciences ,Lineage (genetic) ,Cellular differentiation ,Regulator ,Hematopoietic stem cell ,hemic and immune systems ,Cell Biology ,Biology ,Glutamine ,03 medical and health sciences ,Haematopoiesis ,0302 clinical medicine ,medicine.anatomical_structure ,Biochemistry ,hemic and lymphatic diseases ,medicine ,Genetics ,Molecular Medicine ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Stem cell ,030217 neurology & neurosurgery ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology - Abstract
SummaryThe 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.
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