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Blood, 15 December 2000, Vol. 96, No. 13, pp. 4142-4151
HEMATOPOIESIS
Stromal-derived factor 1 and thrombopoietin regulate distinct
aspects of human megakaryopoiesis
Marcin Majka,
Anna Janowska-Wieczorek,
Janina Ratajczak,
M. Anna Kowalska,
Gaston Vilaire,
Zhixing K. Pan,
Marek Honczarenko,
Leah A. Marquez,
Mortimer Poncz, and
Mariusz Z. Ratajczak
From the Department of Pathology and Laboratory
Medicine and the Department of Pediatrics, University of Pennsylvania
School of Medicine, Philadelphia, PA; the Department of Medicine,
University of Alberta, and Canadian Blood Services, Edmonton, Alberta,
Canada; and the Department of Molecular and Experimental Medicine, The
Scripps Research Institute, La Jolla, CA.
The role of the chemokine binding stromal-derived factor 1 (SDF-1)
in normal human megakaryopoiesis at the cellular and molecular levels
and its comparison with that of thrombopoietin (TPO) have not been
determined. In this study it was found that SDF-1, unlike TPO, does not
stimulate  IIb 3+ cell
proliferation or differentiation or have an antiapoptotic effect.
However, it does induce chemotaxis, trans-Matrigel migration, and secretion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO
increase the adhesion of
IIb3+ cells to fibrinogen and
vitronectin. Investigating the intracellular signaling pathways induced
by SDF-1 and TPO revealed some overlapping patterns of protein
phosphorylation/activation (mitogen-activated protein kinase [MAPK]
p42/44, MAPK p38, and AKT [protein kinase B]) and some that were
distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF- B). It was
also found that though inhibition of phosphatidyl-inositol 3-kinase
(PI-3K) by LY294002 in
IIb3+ cells induced apoptosis
and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF,
the inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no
effect on the survival, proliferation, and migration of these cells.
Hence, it is suggested that the proliferative effect of TPO is more
related to activation of the JAK-STAT pathway (unique to TPO), and the
PI-3K-AKT axis is differentially involved in TPO- and SDF-1-dependent
signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of
apoptosis, TPO- and SDF-1-regulated adhesion to fibrinogen and
vitronectin, and SDF-1-mediated migration. This study expands the
understanding of the role of SDF-1 and TPO in normal human
megakaryopoiesis and indicates the molecular basis of the observed
differences in cellular responses.
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