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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3573-3578
HEMATOPOIESIS
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
Kenneth Kaushansky,
Norma Fox,
Nancy L. Lin, and
W. Conrad Liles
From the University of Washington School of Medicine,
Divisions of Hematology and Infectious Diseases, Seattle, WA.
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
(TGR). This experiment also
allowed us to test the hypothesis that G-CSF contributes to the
residual platelet production in T mice. We
found that TGR 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 TGR 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.
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