TY - JOUR
T1 - Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification
AU - Oburoglu, Leal
AU - Tardito, Saverio
AU - Fritz, Vanessa
AU - De Barros, Stéphanie C.
AU - Merida, Peggy
AU - Craveiro, Marco
AU - Inacio Mamede, Joao Filipe
AU - Cretenet, Gaspard
AU - Mongellaz, Cédric
AU - An, Xiuli
AU - Klysz, Dorota
AU - Touhami, Jawida
AU - Boyer-Clavel, Myriam
AU - Battini, Jean Luc
AU - Dardalhon, Valérie
AU - Zimmermann, Valérie S.
AU - Mohandas, Narla
AU - Gottlieb, Eyal
AU - Sitbon, Marc
AU - Kinet, Sandrina
AU - Taylor, Naomi
N1 - Funding Information:
We thank all members of our laboratories for discussions, scientific critique, and continual support. We are indebted to the maternity staff at the Clinique St. Roch, Montpellier, for their precious assistance and continual support. We are indebted to Alfred Singer and David Scadden for their important insights and critical input. We are very grateful to Megan Bywater, Cathy Wilson, and Gerard Evan for sharing their expertise on the relationship between Myc and metabolic function and to Lise Willems and Didier Bouscary for their assistance with SLC1A5 shRNA plasmids. We thank Montpellier Rio Imaging and the RAM animal facility for assistance with cytometry and animal experiments, respectively. L.O. and G.C. have been supported by a fellowship from the Ligue Contre le Cancer. L.O. is presently supported by the Association de la Recherche contre le Cancer (ARC), S.T. by an AIRC/Marie Curie International Fellowship for Cancer Research, V.F. and S.d.B. by the AFM, P.M. by a grant from the Fondation de la Recherche Médicale, M.C. and J.M. by the Portuguese Foundation for Science and Technology, and D.K. by an EU Marie Curie grant (ATTRACT). C.M., V.D., V.Z., S.K., and M.B.-C. are supported by CNRS, E.G. by Cancer Research UK, and J.-L.B., M.S., and N.T. by INSERM. This work was supported by generous funding from a French national (ANR) research grant GlutStem, the ARC, the AFMTelethon, the Fondation de la Recherche Médicale, la Ligue contre le Cancer, INCA, and the French laboratories of excellence (Labex) GR-Ex (ANR-11-LABX-0051) and EpiGenMed.
PY - 2014/8/7
Y1 - 2014/8/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84905921360&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905921360&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2014.06.002
DO - 10.1016/j.stem.2014.06.002
M3 - Article
C2 - 24953180
AN - SCOPUS:84905921360
SN - 1934-5909
VL - 15
SP - 169
EP - 184
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 2
ER -