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Mice lacking granulocyte colony-stimulating factor have chronic
neutropenia, granulocyte and macrophage progenitor cell deficiency, and
impaired neutrophil mobilization
GJ Lieschke, D Grail, G Hodgson, D Metcalf, E Stanley, C Cheers, KJ Fowler, S Basu, YF Zhan and AR Dunn
Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research,
Parkville, Victoria, Australia.
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.
Volume 84,
Issue 6,
pp. 1737-1746,
09/15/1994
Copyright © 1994 by The American Society of Hematology
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