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Thrombopoietin, but not erythropoietin, directly stimulates multilineage
growth of primitive murine bone marrow progenitor cells in synergy with
early acting cytokines: distinct interactions with the ligands for c-kit
and FLT3
V Ramsfjell, OJ Borge, OP Veiby, J Cardier, MJ Murphy , SD Lyman, S Lok and SE Jacobsen
Hipple Cancer Research Center, Dayton, OH, USA.
Thrombopoietin (Tpo), the ligand for c-mpl, has been shown to be the
principal regulator of megakaryocytopoiesis and platelet production. The
ability of Tpo to potently stimulate the growth of committed megakaryocyte
(Mk) progenitor cells has been studied in detail. Murine fetal liver cells,
highly enriched in primitive progenitors, have been shown to express c-mpl,
but little is known about the ability of Tpo to stimulate the growth and
differentiation of primitive multipotent bone marrow (BM) progenitor cells.
Here, we show that Tpo alone and in combination with early acting cytokines
can stimulate the growth and multilineage differentiation of Lin- Sca-1+ BM
progenitor cells. In particular, Tpo potently synergized with the ligands
for c-kit (stem cell factor [SCF]) and flt3 (FL) to stimulate an increase
in the number and size of clones formed from Lin- Sca-1+ progenitors. When
cells were plated at 1 cell per well, the synergistic effect of Tpo was
observed both in fetal calf serum-supplemented and serum-depleted medium
and was decreased if the addition of Tpo to cultures was delayed for as
little as 24 hours, suggesting that Tpo is acting directly on the primitive
progenitors. Tpo added to SCF + erythropoietin (Epo)-supplemented
methylcellulose cultures potently enhanced the formation of multilineage
colonies containing granulocytes, macrophages, erythrocytes, and Mks. SCF
potently enhanced Tpo-stimulated production of high-ploidy Mks from Lin-
Sca-1+ progenitors, whereas the increased growth response obtained when
combining Tpo with FL did not translate into increased Mk production. The
ability of Tpo and SCF to synergistically enhance the growth of Lin- Sca-1+
progenitors was predominantly observed in the more primitive rhodamine
123(lo) fraction. Tpo also enhanced growth of Lin- Sca-1+ progenitors when
combined with interleukin-3 (IL-3) and IL-11 but not with IL-12,
granulocyte colony-stimulating factor, granulocyte-macrophage colony-
stimulating factor, or Epo. Epo, which has high homology to Tpo, was unable
to stimulate the growth of Lin- Sca-1+ progenitors alone or in combination
with SCF or FL, suggesting that c-mpl is expressed on more primitive stages
of progenitors than the Epo receptor. Thus, the present studies show the
potent ability of Tpo to enhance the growth of primitive multipotent murine
BM progenitors in combination with multiple early acting cytokines and
documents its unique ability to synergize with SCF to enhance Mk production
from such progenitors.
Volume 88,
Issue 12,
pp. 4481-4492,
12/15/1996
Copyright © 1996 by The American Society of Hematology
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