MICE LACKING GRANULOCYTE-COLONY-STIMULATING FACTOR HAVE CHRONIC NEUTROPENIA, GRANULOCYTE AND MACROPHAGE PROGENITOR-CELL DEFICIENCY, AND IMPAIRED NEUTROPHIL MOBILIZATION

Lieschke, GJ; Grail, D; Hodgson, G; Metcalf, D; Stanley, E; Cheers, C; Fowler, KJ; Basu, S; Zhan, YF; Dunn, AR

Author(s): Lieschke, GJ; Grail, D; Hodgson, G; Metcalf, D; Stanley, E; Cheers, C; Fowler, KJ; Basu, S; Zhan, YF; Dunn, AR;
Details: Publication Year 1994-09-15,Volume 84,Issue #6,Page 1737-1746
Journal Title: BLOOD
Publication Type: Journal Article
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. (C) 1994 by The American Society of Hematology.
Publisher: W B SAUNDERS CO
Keywords: INVIVO; GENE; MOUSE; CSF; GRANULOPOIESIS; INFECTION; MUTATION
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Creation Date: 1994-09-15 12:00:00