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Effects of Cytokines on Platelet Production From Blood and Marrow
CD34+ Cells
Françoise Norol,
Natacha Vitrat,
Elisabeth Cramer,
Josette Guichard,
Samuel A. Burstein,
William Vainchenker, and
Najet Debili
From INSERM U 91, Hôpital Henri Mondor, Créteil, France.
The late stages of megakaryocytopoiesis, consisting of the terminal
processes of cytoplasmic maturation and platelet shedding, remain
poorly understood. A simple liquid culture system using CD34+ cells in serum-free medium has been developed to
study the regulation of platelet production in vitro. Platelets
produced in vitro were enumerated by flow cytometry. A truncated form
of human Mpl-Ligand conjugated to polyethylene glycol (PEG-rHuMGDF)
played a crucial role in both proplatelet formation and platelet
production. A combination of stem cell factor (SCF), interleukin-3
(IL-3), and IL-6 was as potent as PEG-rHuMGDF for the growth of
megakaryocytes (MKs). However, the number of proplatelet-displaying MKs
and platelets was increased 10-fold when PEG-rHuMGDF was used.
Peripheral blood mobilized CD34+ cells gave rise to a
threefold augmentation of platelets compared with marrow
CD34+ cells. This finding was related to the higher
proliferative capacity of the former population because the proportion
of proplatelet-displaying MKs was similar for both types of
CD34+ cells. The production of platelets per MK from
CD34+ cells was low, perhaps because of the low ploidy of
the cultured MKs. This defect in polyploidization correlated with the
degree of proliferation of MK progenitors induced by cytokines. In
contrast, ploidy development closer to that observed in marrow MKs was
observed in MKs derived from the low proliferative CD34+
CD41+ progenitors and was associated with a twofold to
threefold increment in platelet production per MK. As shown using this
CD34+ CD41+ cell population, PEG-rHuMGDF
was required throughout the culture period to potently promote platelet
production, but was not involved directly in the process of platelet
shedding. IL-3, SCF, and IL-6 alone had a very weak effect on
proplatelet formation and platelet shedding. Surprisingly, when used in
combination, these cytokines elicited a degree of platelet production
which was decreased only 2.4-fold in comparison with PEG-rHuMGDF. This
suggests that proplatelet formation may be inhibited by non-MK cells
which contaminate the cultures when the entire CD34+ cell
population is used. Cultured platelets derived from PEG-rHuMGDF- or
cytokine combination-stimulated cultures had similar ultrastructural features and a nearly similar response to activation by thrombin. The
data show that this culture system may be useful to study the effects
of cytokines and the role of polyploidization on platelet production
and function.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 830-843
© 1998 by The American Society of Hematology.
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