Lineage-specific growth factors can compensate for stem and progenitor cell deficiencies at the postprogenitor cell level: an analysis of doubly TPO- and G-CSF receptor-deficient mice.
Multiple lines of evidence indicate that thrombopoietin (TPO) substantially impacts the number of hematopoietic stem cells and progenitors of all myeloid lineages. Nevertheless, tpo knock-out mice (T(-)) display thrombocytopenia only; blood erythroid and neutrophil levels are normal despite 60% to 85% reductions in stem and progenitor cells. The compensatory mechanism(s) for these deficiencies remains uncertain; lineage-specific cytokines such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) have been postulated but never proven to be responsible. To directly test whether G-CSF can compensate for the myeloid progenitor cell reduction in the T(-) model of hematopoietic deficiency, T(-) and G-CSF-receptor knock-out (GR(-)) mice were crossed, and F1 animals bred to obtain doubly nullizygous mice (T(-)GR(-)). This experiment also allowed us to test the hypothesis that G-CSF contributes to the residual platelet production in T(-) mice. We found that T(-)GR(-) F2 mice displayed similar blood platelet levels as that seen in T(-) mice, indicating that G-CSF does not account for the residual megakaryopoiesis in T(-) mice. However, we also noted excessive perinatal mortality of T(-)GR(-) animals, caused by infection due to a profound and significant decrease in marrow and peripheral blood neutrophils, far greater than that seen in either T(-) or GR(-) mice. These data indicate that in the additional absence of GR, T(-) mice cannot compensate for their 62% reduction in myeloid progenitors and become profoundly neutropenic, supporting the hypothesis that G-CSF can compensate for the myeloid effects of TPO deficiency by expanding the pool of cells between the granulocyte-macrophage colony-forming unit and mature neutrophil stages of granulopoiesis.
Kaushansky
Kenneth
K
University of Washington School of Medicine, Divisions of Hematology and Infectious Diseases, Seattle, WA 98195, USA. kkaushan@u.washington.edu
Fox
Norma
N
Lin
Nancy L
NL
Liles
W Conrad
WC
D000818:Animals; D019070:Cell Lineage; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000502:physiology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D007958:Leukocyte Count; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D010976:Platelet Count; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D016019:Survival Analysis; D013926:Thrombopoietin / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D013926:Thrombopoietin