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Combined signaling through interleukin-7 receptors and flt3 but not c- kit
potently and selectively promotes B-cell commitment and differentiation
from uncommitted murine bone marrow progenitor cells
OP Veiby, SD Lyman and SE Jacobsen
Blood Cell Growth Factors Laboratory, Hipple Cancer Research Center,
Dayton, OH 45439, USA.
Multiple cytokines can synergize to stimulate the in vitro proliferation
and exclusive myeloid differentiation of multipotent bone marrow progenitor
cells. The ligand for c-kit (stem cell factor [SCF]) plays a key role in
stimulating myeloid and erythroid cell production of primitive
hematopoietic progenitors. SCF in combination with interleukin-7 (IL-7) can
also stimulate the combined myeloid and B-cell differentiation of
uncommitted hematopoietic progenitor cells as well as the growth of early
B-cell progenitor cells, although the involvement of c-kit in early B
lymphopoiesis remains controversial. In the present study, the flt3-ligand
(FL), which, in combination with other cytokines, has overlapping
activities with SCF on myeloid cell production from uncommitted
progenitors, was investigated for its ability to induce selective
stroma-independent B-cell commitment from uncommitted Lin-Sca-1+ bone
marrow progenitor cells. IL-7 alone did not induce any clonal growth and FL
alone gave rise to a few clusters (< 50 cells) but no colonies (> 50
cells), whereas the combined stimulation with FL and IL-7 resulted in
clonal growth of 10% of Lin-Sca-1+ bone marrow cells. After 12 days of
incubation of Lin-Sca-1+ cells in FL + IL-7, an almost 400-fold increase in
cell production was observed. Phenotyping showed that greater than 99% of
the cells produced were of the B-cell lineage, in that they expressed B220,
but not cell surface markers specific for myeloid, erythroid, or T-cell
lineages. Furthermore, the cells did not express cytoplasmic mu-heavy chain
(cmu) or surface IgM, but were positive for CD24 (heat stable antigen
[HSA]) and CD43 (leukosialin), suggesting that the cells produced were
blocked at a late pro-B-cell stage. Interestingly, although all FL + IL-7-
responsive Lin-Sca-1+ progenitor cells and the resulting pro-B cells
expressed c-kit, FL + IL-7 was much more potent (62-fold) than SCF + IL- 7
in stimulating production of cells of the B-cell lineage. In addition,
whereas FL + IL-7 selectively stimulated the production of pro-B cells, SCF
+ IL-7 predominantly stimulated the production of mature granulocytes.
Replating studies showed that FL + IL-7-responsive Lin-Sca-1+ progenitors
were not committed to the B-cell lineage, because after 2 days of
incubation in FL + IL-7, 80% of the progenitors retained a myeloid
potential. As much as 27% of the FL + IL-7- responsive progenitors remained
uncommitted after 7 days of incubation, but all had committed to the B-cell
lineage after 10 days of incubation in FL + IL-7. These results show that
FL much more potently and selectively than SCF synergizes with IL-7 to
enhance B-cell commitment and development from uncommitted progenitor
cells.
Volume 88,
Issue 4,
pp. 1256-1265,
08/15/1996
Copyright © 1996 by The American Society of Hematology
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