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Effects of the recombinant hematopoietic growth factors interleukin-3,
interleukin-6, stem cell factor, and leukemia inhibitory factor on the
megakaryocytic differentiation of CD34+ cells
N Debili, JM Masse, A Katz, J Guichard, J Breton-Gorius and W Vainchenker
INSERM U 91, Hopital Henri Mondor, Creteil, France.
Using a liquid culture system and human CD34+ marrow cells, we examined the
effects of recombinant interleukin (IL)-3, IL-6, stem cell factor (SCF),
and leukemia inhibitory factor (LIF) on megakaryocyte (MK) growth,
endoreplication, and maturation. MK proliferation, ploidy distribution, and
volume were studied by flow cytometry. IL-3 was the only cytokine that,
alone, induced a marked increase in MK proliferation. At a high CD34+ cell
concentration, addition of IL-6, SCF, and LIF to IL-3--containing medium
increased the number of MK (approximately 20%). At a low CD34+ cell
concentration, IL-3 alone was a less potent inducer of MK growth, but IL-6,
SCF, and their combination had a marked effect, increasing the number of MK
by a factor 1.7, 2.9, and 4.4, respectively. These differences may be
related to the endogenous release of cytokines in the culture. The effects
of these cytokines were subsequently tested on a more mature type of MK
progenitor (CD34+ cells isolated after 6 days of incubation in liquid
culture). IL-3 remained the most potent cytokine, but IL-6 or SCF alone
also increased MK number in comparison to unstimulated cultures. The ploidy
distribution of MKs grown with IL-3 was not markedly changed by the
addition of the other cytokines, with the exception of SCF, which induced a
significant increase in the mean ploidy. However, in all cultures,
glycoprotein (GP)IIIa+ 2N and 4N cells were present in large but variable
numbers (35% to 75%). The number of these low-ploidy MKs directly
correlated with MK proliferation. Therefore, we subsequently explored the
absolute number of polyploid MK produced in culture. SCF, IL-6, or their
combination, in association with IL-3, increased the number of polyploid MK
up to fourfold. In addition, they improved the maturation of MK grown in
the presence of IL-3, leading to the synthesis of demarcation membranes and
platelet shedding. A similar effect of growth factors on the maturation of
day 6 CD34+ cells was observed. We conclude that IL-6 and SCF have a broad
range of activities on megakaryocytopoiesis, acting both on the early and
late stages. However, the proliferative properties of these cytokines
largely predominate in our cultures. Therefore, in the absence of a
specific MK regulator, this study further extends the need for a
combination of growth factors to maximize megakaryocytopoiesis.
Volume 82,
Issue 1,
pp. 84-95,
07/01/1993
Copyright © 1993 by The American Society of Hematology
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