title: A novel role for PECAM-1 in megakaryocytokinesis and recovery of platelet counts in thrombocytopenic mice.
abstract: During thrombopoiesis, maturing megakaryocytes (MKs) migrate within the complex bone marrow stromal microenvironment from the proliferative osteoblastic niche to the capillary-rich vascular niche where proplatelet formation and platelet release occurs. This physiologic 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 polarization of the SDF1 receptor CXCR4 and an increase in adhesion to immobilized 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 localization 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.
authors.affiliation: Centre for Cardiovascular Sciences, Institute of Biomedical Research, Division of Medical Sciences, The Medical School, University of Birmingham, Birmingham, United Kingdom. t.s.dhanjal@bham.ac.uk
authors.forename: Tarvinder S
authors.initials: TS
authors.lastname: Dhanjal
authors.forename: Caroline
authors.initials: C
authors.lastname: Pendaries
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Ross
authors.forename: Mark K
authors.initials: MK
authors.lastname: Larson
authors.forename: Majd B
authors.initials: MB
authors.lastname: Protty
authors.forename: Chris D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D048749:Cytokinesis; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010976:Platelet Count; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000378:metabolism / Q000502:physiology; D013921:Thrombocytopenia / Q000235:genetics*
chemical_list: C514936:CXCR4 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019718:Receptors, CXCR4