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Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 769-775
Stromal cell-derived factor-1 (SDF-1) acts together with
thrombopoietin to enhance the development of megakaryocytic progenitor
cells (CFU-MK)
Keiko Hodohara,
Nobutaka Fujii,
Naoki Yamamoto, and
Kenneth Kaushansky
Division of Hematology, University of Washington School of Medicine;
Faculty of Pharmaceutical Science, Kyoto University; Department of
Microbiology, Tokyo Medical and Dental University School of Medicine.
Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that acts
as a stimulator of pre-B lymphocyte cell growth and as a
chemoattractant for T cells, monocytes, and hematopoietic stem cells.
More recent studies also suggest that megakaryocytes migrate in
response to SDF-1. Because genetic elimination of SDF-1 or its receptor
lead to marrow aplasia, we investigated the effect of SDF-1 on
megakaryocyte progenitors (colony-forming units-megakaryocyte [CFU-MK]). We report that SDF-1 augments the growth of CFU-MK from
whole murine bone marrow cells when combined with thrombopoietin (TPO).
The addition of SDF-1 to interleukin-3 (IL-3) or stem cell factor (SCF)
had no effect. Specific antagonists for CXCR4 (the sole receptor for
SDF-1), T22, and 1-9 (P2G) SDF-1 reduced megakaryocyte colony growth
induced by TPO alone, suggesting that many culture systems contain
endogenous levels of the chemokine that contributes to the TPO effect.
To examine whether SDF-1 has direct effects on CFU-MK, we developed a
new protocol to purify megakaryocyte progenitors. CFU-MK were highly
enriched in CD41high c-kithigh cells generated
from lineage-depleted TPO-primed marrow cells. Because the
growth-promoting effects of SDF-1 were also observed when highly
purified populations of CFU-MK were tested in serum-free cultures,
these results suggest that SDF-1 directly promotes the proliferation of
megakaryocytic progenitors in the presence of TPO, and in this way
contributes to the favorable effects of the bone marrow
microenvironment on megakaryocyte development.
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