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Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel
factor and other early acting cytokines in supporting proliferation of
primitive hematopoietic progenitors of mice
H Ku, Y Yonemura, K Kaushansky and M Ogawa
Department of Medicine, Medical University of South Carolina, Charleston,
USA.
Recently, the ligand for the Mpl receptor (ML) was identified to be
thrombopoietin, the principal regulator of megakaryocytopoiesis and
thrombopoiesis. We examined the effects of ML, as a single factor or in
combinations with early acting factors such as steel factor (SF),
interleukin (IL)-3, IL-1, IL-6, and granulocyte colony-stimulating factor
(G-CSF), on colony formation from primitive progenitors of mice. Cells
enriched for cell cycle dormant primitive progenitors were isolated from
bone marrow cells of 5-fluorouracil (5-FU)-treated mice by a combination of
Nycodenz density gradient separation, immunomagnetic selection for
lineage-negative cells, and fluorescence- activated cell sorter (FACS)
sorting for Ly-6A/E+Kit+ cells. ML, in the presence of erythropoietin,
could support the formation of only a few megakaryocyte colonies. However,
ML acted synergistically with SF or IL- 3 to support the formation of
multiple types of hematopoietic colonies including multilineage colonies.
Effects of the combination of ML and SF on multipotential progenitors were
not mediated through other cells, as demonstrated by micromanipulation of
individual progenitors. In suspension culture, the combination of ML and SF
increased the number of multipotential progenitors. ML also acted
synergistically with IL- 11, IL-6, or G-CSF to support colony formation in
serum-containing, but not in serum-free, cultures. However, the
multilineage colony formation seen in serum-containing culture was
completely abrogated by addition of ACK2, a neutralizing antibody to Kit
protein. Serial observation (mapping studies) of colony development from
multipotential progenitors suggested that ML triggers the cell division of
dormant progenitors. Based on these observations, we propose that ML can
function as an early acting cytokine and stimulate the proliferation of
cell cycle dormant progenitors by shortening their G0 period.
Volume 87,
Issue 11,
pp. 4544-4551,
06/01/1996
Copyright © 1996 by The American Society of Hematology
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