G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling

Leukemia. 2014 Sep;28(9):1851-60. doi: 10.1038/leu.2014.68. Epub 2014 Feb 12.


Recent studies demonstrate that inflammatory signals regulate hematopoietic stem cells (HSCs). Granulocyte colony-stimulating factor (G-CSF) is often induced with infection and has a key role in the stress granulopoiesis response. However, its effects on HSCs are less clear. Herein, we show that treatment with G-CSF induces expansion and increased quiescence of phenotypic HSCs, but causes a marked, cell-autonomous HSC repopulating defect associated with induction of Toll-like receptor (TLR) expression and signaling. The G-CSF-mediated expansion of HSCs is reduced in mice lacking TLR2, TLR4 or the TLR signaling adaptor MyD88. Induction of HSC quiescence is abrogated in mice lacking MyD88 or in mice treated with antibiotics to suppress intestinal flora. Finally, loss of TLR4 or germ-free conditions mitigates the G-CSF-mediated HSC repopulating defect. These data suggest that low-level TLR agonist production by commensal flora contributes to the regulation of HSC function and that G-CSF negatively regulates HSCs, in part, by enhancing TLR signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / physiology
  • Intestines / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / physiology
  • Receptors, Granulocyte Colony-Stimulating Factor / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Toll-Like Receptors / physiology*
  • fms-Like Tyrosine Kinase 3 / physiology


  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Toll-Like Receptors
  • Granulocyte Colony-Stimulating Factor
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3