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

Graham J. Lieschke, Dianne Grail, George Hodgson, Donald Metcalf, Edouard Stanley, Christina Cheers, Kerry J. Fowler, Sunanda Basu, Yi F. Zhan, Ashley R. Dunn

Research output: Contribution to journalArticleResearchpeer-review

693 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1737-1746
Number of pages10
JournalBlood
Volume84
Issue number6
Publication statusPublished - 15 Sep 1994
Externally publishedYes

Cite this