title: G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling.
abstract: 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.
authors: Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
authors: L G
authors: LG
authors: Schuettpelz
authors: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
authors: J N
authors: JN
authors: Borgerding
authors: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
authors: M J
authors: MJ
authors: Christopher
authors: Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: P K
authors: PK
authors: Gopalan
authors: Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
authors: M P
authors: MP
authors: Romine
authors: Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, USA.
authors: A C
authors: AC
authors: Herman
authors: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
authors: J R
authors: JR
authors: Woloszynek
authors: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
authors: A M
authors: AM
authors: Greenbaum
authors: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO, USA.
authors: D C
authors: DC
authors: Link
mesh_terms: D000818:Animals; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D007422:Intestines / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology*; D051941:fms-Like Tyrosine Kinase 3 / Q000502:physiology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D051193:Toll-Like Receptors; D016179:Granulocyte Colony-Stimulating Factor; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3