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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3915-3923
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Megakaryocytes require thrombospondin-2 for normal
platelet formation and function
Themis R. Kyriakides,
Ponlapat Rojnuckarin,
Michael A. Reidy,
Kurt D. Hankenson,
Thalia Papayannopoulou,
Kenneth Kaushansky, and
Paul Bornstein
From the Departments of Biochemistry, Pathology, and
Medicine, and the Division of Hematology, University of Washington,
Seattle, WA.
Mice that lack the matricellular angiogenesis inhibitor,
thrombospondin-2 (TSP2), display a bleeding diathesis, despite normal blood coagulation and the lack of thrombocytopenia. Although platelets do not contain detectable levels of TSP2, TSP2-null platelets are
compromised in their ability to aggregate in vivo in response to
denudation of the carotid artery endothelium, and in vitro following
exposure to adenosine diphosphate (ADP). Megakaryocytes (MKs)
show high levels of TSP2 by immunohistochemical analysis of
bone marrow. However, when cultured in vitro, MKs contain little TSP2
protein or mRNA. These findings suggest that most TSP2 is acquired from
the bone marrow microenvironment. Consistent with this hypothesis, MKs
take up recombinant TSP2 in an integrin-dependent manner when it is
supplied in the culture medium. Furthermore, uptake of TSP2 in vitro
affects MK differentiation and proplatelet formation. The functional
significance of this process is supported by the presence of
ultrastructural abnormalities in TSP2-null bone marrow, including
extensive fragmentation of the peripheral zone in MKs and failure of
this zone to form close associations with vascular sinuses. We conclude
that the uptake of TSP2 by MKs from the marrow milieu is required for
proper MK function and the release of functionally competent platelets.
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