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The effect of thrombopoietin on the proliferation and differentiation of
murine hematopoietic stem cells
E Sitnicka, N Lin, GV Priestley, N Fox, VC Broudy, NS Wolf and K Kaushansky
Department of Pathology and Division of Hematology, School of Medicine,
University of Washington, Seattle, WA, USA.
In this study, we explored whether thrombopoietin (Tpo) has a direct in
vitro effect on the proliferation and differentiation of long-term
repopulating hematopoietic stem cells (LTR-HSC). We previously reported a
cell separation method that uses the fluorescence-activated cell sorter
selection of low Hoescht 33342/low Rhodamine 123 (low Ho/low Rh)
fluorescence cell fractions that are highly enriched for LTR-HSC and can
reconstitute lethally irradiated recipients with fewer than 20 cells. Low
Ho/low Rh cells clone with high proliferative potential in vitro in the
presence of stem cell factor (SCF) + interleukin-3 (IL-3) + IL-6 (90% to
100% HPP-CFC). Tpo alone did not induce proliferation of these low Ho/low
Rh cells. However, in combination with SCF or IL-3, Tpo had several
synergistic effects on cell proliferation. When Tpo was added to single
growth factors (either SCF or IL-3 or the combination of both), the time
required for the first cell division of low Ho/low Rh cells was
significantly shortened and their cloning efficiency increased
substantially. Moreover, the subsequent clonal expansion at the early time
points of culture was significantly augmented by Tpo. Low Ho/low Rh cells,
when assayed in agar directly after sorting, did not form megakaryocyte
colonies in any growth condition tested. Several days of culture in the
presence of multiple cytokines were required to obtain colony-forming
units-megakaryocyte (CFU-Mk). In contrast, more differentiated, low Ho/high
Rh cells, previously shown to contain short- term repopulating
hematopoietic stem cells (STR-HSC), were able to form megakaryocyte
colonies in agar when cultured in Tpo alone directly after sorting. These
data establish that Tpo acts directly on primitive hematopoietic stem cells
selected using the Ho/Rh method, but this effect is dependent on the
presence of pluripotent cytokines. These cells subsequently differentiate
into CFU-Mk, which are capable of responding to Tpo alone. Together with
the results of previous reports of its effects on erythroid progenitors,
these results suggest that the effects of Tpo on hematopoiesis are greater
than initially anticipated.
Volume 87,
Issue 12,
pp. 4998-5005,
06/15/1996
Copyright © 1996 by The American Society of Hematology
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