Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization

Blood. 1994 Sep 15;84(6):1737-46.

Abstract

Mice lacking granulocyte colony-stimulating factor (G-CSF) were generated by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and superficially healthy, but have a chronic neutropenia. Peripheral blood neutrophil levels were 20% to 30% of wild-type mice (genotype G-CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophil levels, suggesting a gene-dosage effect. In the marrow of G-CSF-/- mice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells. Despite G-CSF deficiency, mature neutrophils were still present in the blood and marrow, indicating that other factors can support neutrophil production in vivo. G-CSF-/- mice had reduced numbers of neutrophils available for rapid mobilization into the circulation by a single dose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice elevated circulating neutrophil levels to normal, and after 4 days of G-CSF administration, G-CSF+/+ and G-CSF-/- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to control infection with Listeria monocytogenes, with diminished neutrophil and delayed monocyte increases in the blood and reduced infection-driven granulopoiesis. Collectively, these observations indicate that G-CSF is indispensible for maintaining the normal quantitative balance of neutrophil production during "steady-state" granulopoiesis in vivo and also implicate G-CSF in "emergency" granulopoiesis during infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Genotype
  • Granulocyte Colony-Stimulating Factor / deficiency*
  • Granulocyte Colony-Stimulating Factor / genetics
  • Granulocyte Colony-Stimulating Factor / pharmacology
  • Granulocytes / pathology*
  • Hematopoiesis
  • Hematopoietic Stem Cells / parasitology*
  • Leukocyte Count
  • Listeriosis / pathology
  • Macrophages / pathology*
  • Mice
  • Molecular Sequence Data
  • Neutropenia / etiology*
  • Neutrophils / physiology*

Substances

  • Granulocyte Colony-Stimulating Factor