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Thrombopoietin Requires Additional Megakaryocyte-Active Cytokines
for Optimal Ex Vivo Expansion of Megakaryocyte Precursor Cells
J. Lynne Williams,
George G. Pipia,
Nabanita S. Datta, and
Michael
W. Long
From Oakland University, Rochester, MI; and the Department of
Pediatrics and the Comprehensive Cancer Center, University of Michigan,
Ann Arbor.
Little is known concerning the interaction of thrombopoietin (TPO)
with other megakaryocyte-active cytokines in directing the early events
of megakaryocyte development. Culture of CD34+ cells in
interleukins (IL) -1, -6, -11, plus stem cell factor (SCF;
S) results in a 10- to 12-fold expansion in total cell
numbers, whereas total CD41+ megakaryocytes are expanded
~120-fold over input levels. Addition of TPO to IL-1, -6, -11, S
generates a biphasic proliferation of CD41+ cells,
accelerates their rate of production, and results in an ex vivo
expansion of more than 200-fold. The addition of Flt-3 ligand (FL)
increases CD41+ cell expansion to ~380-fold over input
levels. In the absence of TPO, ~95% of the expanded cells show the
phenotype of promegakaryoblasts; TPO and/or FL addition
increases CD41 antigen density and ploidy in a subpopulation of
promegakaryoblasts. A moderate (approximately sevenfold) expansion of
megakaryocyte progenitor cells (colony-forming unit-megakaryocyte) occurs in the presence of IL-1, -6, -11, S, and the addition of TPO to this cocktail yields an ~17-fold
expansion. We conclude that early proliferative events in megakaryocyte
development in vitro are regulated by multiple cytokines, and that TPO
markedly affects these early developmental steps. However, by itself,
TPO is neither necessary nor sufficient to generate a full
proliferative/maturational in vitro response within the megakaryocyte
compartment. TPO clearly affects terminal differentiation and the
development of (some) high-ploidy human megakaryocytes. However, its
limited in vitro actions on human cell polyploidization suggest that
additional megakaryocyte-active cytokines or other signals are
essential for the maximal development of human megakaryocytes.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4118-4126
© 1998 by The American Society of Hematology.
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