Platelets in Lymph Vessel Development and Integrity
Blood platelets have recently been proposed to play a critical role in the development and repair of the lymphatic system. The platelet C-type lectin receptor CLEC-2 and its ligand, the transmembrane protein Podoplanin, which is expressed at high levels o
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Platelets in Lymph Vessel Development and Integrity Steve P. Watson, Kate Lowe, and Brenda A. Finney
Abstract Blood platelets have recently been proposed to play a critical role in the development and repair of the lymphatic system. The platelet C-type lectin receptor CLEC-2 and its ligand, the transmembrane protein Podoplanin, which is expressed at high levels on lymphatic endothelial cells (LECs), are required to prevent mixing of the blood and lymphatic vasculatures during mid-gestation. A similar defect is seen in mice deficient in the tyrosine kinase Syk, which plays a vital role in mediating platelet activation by CLEC-2. Furthermore, blood-lymphatic mixing is also present in mice with platelet-/megakaryocyte-specific deletions of CLEC-2 and Syk, suggesting that the phenotype is platelet in origin. The molecular basis of this effect is not known, but it is independent of the major platelet receptors that support hemostasis, including integrin αIIbβ3 (GPIIb-IIIa). Radiation chimeric mice reconstituted with CLEC-2-deficient or Syk-deficient bone marrow exhibit blood-lymphatic mixing in the intestines, illustrating a role for platelets in repair and growth of the lymphatic system. In this review, we describe the events that led to the identification of this novel role of platelets and discuss possible molecular mechanisms and the physiological and pathophysiological significance.
8.1
Introduction
Blood platelets have recently been recognized to play a critical role in the development and repair of the lymphatic system. Activation of the platelet C-type lectin receptor CLEC-2 by the transmembrane protein Podoplanin on lymphatic endothelial cells (LECs) prevents mixing of the blood and the lymphatic vasculatures. This involves a pathway that is independent of the major platelet receptors that support hemostasis, including integrin αIIbβ3 (GPIIb-IIIa). Radiation chimeric mice S.P. Watson (*) • K. Lowe • B.A. Finney Centre for Cardiovascular Sciences, The College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK e-mail: [email protected] F. Kiefer and S. Schulte-Merker (eds.), Developmental Aspects of the Lymphatic Vascular System, Advances in Anatomy, Embryology and Cell Biology 214, DOI 10.1007/978-3-7091-1646-3_8, © Springer-Verlag Wien 2014
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reconstituted with CLEC-2-deficient bone marrow also exhibit blood-lymphatic mixing, illustrating a role in repair and growth of the lymphatic system. We describe the events that led to the identification of this novel role of platelets and discuss hypotheses on the underlying mechanism and the physiological and pathophysiological significance.
8.2
CLEC-2
The C-type lectin receptor CLEC-2 (gene name CLEC-1b) was first described as a transcript in a subpopulation of myeloid cells based on its sequence homology to other C-type lectins (Colonna et al. 2000). Several years later, CLEC-2 was identified in platelets by a combination of affinity chromatography using the snake venom toxin rhodocytin and proteomic
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