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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4237-4244.
Prepublished online as a Blood First Edition Paper on January 18, 2007; DOI 10.1182/blood-2006-10-050740.
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Submitted October 6, 2006
Accepted January 4, 2007
A novel role for PECAM-1 in megakaryocytokinesis and recovery of platelet counts in thrombocytopenic mice
Tarvinder S Dhanjal*, Caroline Pendaries, Ewan A Ross, Mark K Larson, Majd B Protty, Chris D Buckley, and Steve P Watson
Centre for Cardiovascular Sciences, Institute for Biomedical Research, The Medical School, University of Birmingham, Birmingham, United Kingdom
Rheumatology Research Group, Institute for Biomedical Research, The Medical School, University of Birmingham, Birmingham, United Kingdom
* Corresponding author; email: t.s.dhanjal{at}bham.ac.uk.
During thrombopoiesis, maturing megakaryocytes (MKs) migrate within the complex bone marrow stromal micro-environment from the proliferative osteoblastic niche to the capillary rich vascular niche where proplatelet formation and platelet release occurs. This physiological process involves proliferation, differentiation, migration and maturation of MKs before platelet production occurs. In this study, we report a role for the glycoprotein PECAM-1 in thrombopoiesis. We show that, following induced thrombocytopenia, recovery of the peripheral platelet count is impaired in PECAM-1 deficient mice. Whereas MK maturation, proplatelet formation and platelet production under in vitro conditions were unaffected, we identified a migration defect in PECAM-1 deficient MKs in response to a gradient of stromal cell derived factor 1 (SDF1), a major chemokine regulating MK migration within the bone marrow. This defect could be explained by defective PECAM-1-/- MK polarisation of the SDF1 receptor CXCR4 and an increase in adhesion to immobilised bone marrow matrix proteins that can be explained by an increase in integrin activation. The defect of migration and polarization was confirmed in vivo with demonstration of altered spatial localisation of MKs within the bone marrow in PECAM-1-deficient mice, following immune-induced thrombocytopenia. This study identifies a novel role for PECAM-1 in regulating MK migration and thrombopoiesis.
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