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Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand
N Banu, JF Wang, B Deng, JE Groopman and H Avraham
Division of Hematology/Oncology, New England Deaconess Hospital, Harvard
Medical School, Boston, MA 02215, USA.
We have further characterized the biological activities, mechanism of
action, and target cell populations of recombinant human and murine
thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model
systems. Alone, hTPO or mTPO stimulated the maturation of immature murine
megakaryoblasts as measured in a single cell assay. The combination of hTPO
or mTPO and interleukin-6 (IL-6) resulted in a further increase in
megakaryocyte differentiation in this system. Murine TPO stimulated mouse
megakaryocyte progenitor development. Human megakaryocyte progenitor
development was potentiated by hTPO alone and further augmented in the
presence of the early-acting cytokines (IL-3) or kit ligand/stem cell
factor (KL/SCF). To further define the mechanism of action of TPO,
neutralization studies were performed with antisera to IL-3,
granulocyte-macrophage colony-stimulating factor (GM- CSF), IL-1 beta, and
IL-11. No diminution in TPO activity was observed in the presence of these
antisera. Moreover, because adhesive interactions are known to modulate
hematopoiesis, we studied whether hTPO might alter such interactions
between human bone marrow (BM) megakaryocytes and human BM stromal
fibroblasts. No changes were observed in either megakaryocyte expression of
the surface molecules lymphocyte function-associated antigen-1, very late
activation antigen- 4, or intercellular adhesion molecule-1 or the adhesion
of megakaryocytes to stromal fibroblasts after treatment with the growth
factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha,
IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor- alpha,
transforming growth factor-beta 1, or transforming growth factor- beta 2 by
primary human BM megakaryocytes was noted after treatment of the cells with
hTPO. To address whether TPO affects very primitive hematopoietic
progenitors, we studied the residual cells from the BMs of mice treated
with high doses of 5-fluorouracil. Although no effect of mTPO alone was
noted on the viability or replication of such primitive murine progenitor
populations, the triple combination of IL-3 + KL/SCF + TPO stimulated
growth of megakaryocyte progenitors. These results indicate that TPO is a
highly lineage-specific growth factor whose primary biological effects are
likely to be direct modulation of the growth and maturation of committed
megakaryocyte precursors and immature megakaryoblasts.
Volume 86,
Issue 4,
pp. 1331-1338,
08/15/1995
Copyright © 1995 by The American Society of Hematology
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