Pivotal role of granulocyte colony-stimulating factor in the development of progenitors in the common myeloid pathway

Abstract

Granulocyte colony-stimulating factor (G-CSF) is the principal cytokine regulating granulopoiesis. G-CSF receptor-deficient mice (G-CSFR-/-) are neutropenic but have only a modest reduction of committed myeloid progenitors. Since it is likely that compensatory mechanisms are induced by the severe neutropenia present in G-CSFR-/- mice, a competitive repopulation assay was performed. These data show that under basal conditions, G-CSF drives nearly all of granulopoiesis through multiple mechanisms. Most importantly, G-CSFR signals regulate the production and/or maintenance of committed-myeloid progenitors. Surprisingly, G-CSFR signals also play a significant role in the regulation of primitive multipotential progenitors in vivo. The contribution of G-CSFR-/- cells to the hematopoietic stem cell compartment is modestly reduced. Moreover, a marked decrease in the contribution of G-CSFR-/- cells to other progenitors in the myeloid pathway, including erythroid and megakaryocytic progenitors, is observed. In contrast, relative to the hematopoietic stem cell compartment, the contribution of G-CSFR-/- cells to the lymphoid lineages is increased. These data suggest that G-CSFR signals may play a role in directing the commitment of primitive hematopoietic progenitors to the common myeloid lineage. Thus, regulation of G-CSF levels may provide a mechanism for directing primitive hematopoietic progenitors into the common myeloid lineage in response to environmental stresses. (Blood. 2003; 102:3562-3568)

Neutrophils in cancer: neutral no more

“…Granulocyte-colony stimulating factor (G-CSF) is the master regulator of neutrophil generation and differentiation [15][16][17] . G-CSF acts at the level of myeloid progenitors to induce their proliferation and differentiation.…”

“…If large numbers of neutrophils are used up during infection or cancer, a process called emergency granulopoiesis overtakes steady state granulopoiesis to rapidly increase neutrophil formation 11 . In tumor-bearing mice and humans with pancreatic or colon cancer (and most likely other tumor types), the spleen is an alternative source of neutrophil production 14 .Granulocyte-colony stimulating factor (G-CSF) is the master regulator of neutrophil generation and differentiation [15][16][17] . G-CSF acts at the level of myeloid progenitors to induce their proliferation and differentiation.…”

G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy

“…The dystrophin-utrophin double-knockout male homozygous (dystrophin À /Y (mdx), utrophin À / À ) mice were obtained by crossing those heterozygous (mdx, utrophin þ / À ) mice. The csf3r À / À mice were kindly gifted by Dr Daniel C. Link (Washington University School of Medicine, St Louis) 28 . Mice deficient in both dystrophin and csf3r were derived by the following breeding program: male csf3r-knockout (csf3r À / À ) mice were mated with female C57B/6 mdx (dystrophin À /X ) mice, resulting in all F1-generation mice being heterozygous for csf3r (csf3r þ / À ) and either heterozygous for the mdx mutation (dystrophin À /X , females) or hemizygous for the mdx mutation (dystrophin À /Y , males).…”

“…To clarify the roles of G-CSF in DMD, we next used csf3r À / À mice, which show a slight haematological disorder and a normal lifespan 28,29 . We hypothesized that breeding G-CSFR homozygote-knockout mdx mice (mdx/csf3r À / À ) would produce (Fig.…”

Revisiting Use of Growth Factors in Myelodysplastic Syndromes

“…G-CSF probably has its effect on intermediate myeloblasts and promyelocytes. However, treating AML patients with G-CSF for differentiation induction of blast cells, and increasing their apoptosis had variable results (Richards et al, 2003;Beekman et al, 2010;Gurion et al, 2011).…”