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Interaction of stem cell factor and its receptor c-kit mediates lodgment
and acute expansion of hematopoietic cells in the murine spleen
VC Broudy, NL Lin, GV Priestley, K Nocka and NS Wolf
Department of Medicine University of Washington, Seattle 98195, USA
The phenotypes of mice that harbor a defect in the genes encoding either
stem cell factor (SCF) or its receptor, c-kit, indicate that this
ligand/receptor pair is necessary for maintenance of normal hematopoiesis
in the adult. Our objective was to determine whether SCF, like
erythropoietin, is necessary for acute erythroid expansion during recovery
from hemolytic anemia. Monoclonal antibody ACK2, which recognizes the
murine c-kit receptor, was used to selectively block the hematopoietic
growth-promoting effects of SCF. Mice were treated with phenylhydrazine on
day 0 and day 1 to induce hemolytic anemia and also received no antibody,
control IgG, or ACK2 on day 0. The mice were killed on day 3 and the
hematocrit (Hct), reticulocyte count, and numbers of erythroid and myeloid
hematopoietic progenitor cells (colony- forming unit-erythroid [CFU-E],
burst-forming unit [BFU]-E, and CFU- granulocyte-macrophage [GM]) were
quantitated in the femoral marrow and spleen using hematopoietic
colony-forming assays. Induction of hemolytic anemia with phenylhydrazine
resulted in a drop in the Hct from approximately 50% to 30%, and an
approximate 8- to 10-fold increase in the reticulocyte count. The numbers
of CFU-E increased modestly in the femur, and approximately 25- to 50-fold
in the spleen, in comparison with normal mice. BFU-E and CFU-GM values did
not increase in the femur but expanded 6- to 10-fold in the spleen, in
comparison with normal mice. This confirms that much of the erythroid
expansion in response to hemolytic anemia occurs in the murine spleen.
Neutralizing quantities of the ACK2 antibody reduced femoral CFU-E, BFU- E,
and CFU-GM content to less than half that found in phenylhydrazine- treated
control mice and nearly totally ablated splenic hematopoiesis. These
results suggest that c-kit receptor function may be required for optimal
response to acute erythropoietic demand and that erythropoiesis in the
splenic microenvironment is more dependent on SCF/c-kit receptor
interaction than is erythropoiesis in the marrow microenvironment. Because
expansion of late erythropoiesis in the spleen was preferentially blocked,
we tested the hypothesis that homing of more primitive hematopoietic cells
to the spleen was dependent on c-kit receptor function. Lethally irradiated
mice were injected with marrow cells obtained from mice that had received
phenylhydrazine plus control IgG or with marrow cells obtained from mice
that had received phenylhydrazine plus ACK2. In parallel experiments,
normal murine marrow cells were treated in vitro with control IgG or with
ACK2 and were injected into lethally irradiated mice. The fraction of BFU-E
and CFU-GM retrieved from the marrow and spleen of the recipient mice 4
hours later was reduced by approximately 75% when progenitor cells had been
exposed to ACK2, in comparison with control IgG. These data suggest that
interaction of SCF with the c-kit receptor affects the homing behavior of
hematopoietic progenitor cells in the adult animal.
Volume 88,
Issue 1,
pp. 75-81,
07/01/1996
Copyright © 1996 by The American Society of Hematology
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