Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification

Cell Stem Cell. 2014 Aug 7;15(2):169-84. doi: 10.1016/j.stem.2014.06.002. Epub 2014 Jun 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism
  • Amino Acid Transport System ASC / metabolism*
  • Animals
  • Antigens, CD34 / metabolism
  • Biological Transport
  • Cell Differentiation
  • Cell Lineage*
  • Chromatography, Liquid
  • Erythrocytes / cytology
  • Gene Expression Regulation*
  • Glucose / metabolism*
  • Glutamine / metabolism*
  • Glycolysis
  • Green Fluorescent Proteins / metabolism
  • Hematopoietic Stem Cells / cytology*
  • Humans
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • Minor Histocompatibility Antigens
  • RNA, Small Interfering / metabolism


  • Amino Acid Transport System ASC
  • Antigens, CD34
  • Minor Histocompatibility Antigens
  • RNA, Small Interfering
  • SLC1A5 protein, human
  • Slc1a5 protein, mouse
  • Glutamine
  • Green Fluorescent Proteins
  • ADP-ribosyl Cyclase 1
  • Glucose