MRC National Institute for Medical Research, London
Science for Health
Platelets influence the formation of lymphatic vessels
13 January 2012
Scientists at NIMR and at the University of Birmingham have shown how platelets affect the development of the circulatory system. The research is published in Blood.
The circulatory system comprises the cardiovascular system, which distributes blood, and the lymphatic system, which distributes lymph. In normal development, lymphatic vessels separate from blood vessels during embryogenesis. Recently several mutant mouse models have shown a defect in the separation of the lymphatic vasculature from the blood vasculature, resulting in the appearance of blood-filled lymphatic vessels in the skin. Several years ago, Victor Tybulewicz (pictured) and his lab in NIMR's Division of Immune Cell Biology showed that mice deficient in the tyrosine kinase Syk show this phenotype and die around the time of birth. Since Syk is broadly expressed in the haematopoietic system but not in blood endothelial cells or lymphatic endothelial cells (LECs), it was not known which Syk-expressing cell type was required for normal lymphatic development.
The C-type lectin receptor CLEC-2 is highly expressed on platelets and at lower levels on other haematopoietic cells and has recently been recognised as a receptor for the transmembrane protein Podoplanin, which is expressed on LECs, lung type-1 alveolar cells and kidney podocytes. A series of recent studies has shown that deletion of CLEC-2 or Podoplanin resulted in blood-filled lymphatics in mid-gestation and in perinatal lethality, similar to that seen in Syk-deficient mice. Since CLEC-2 has been shown to signal through Syk, these studies suggest that separation of the lymphatics from blood vessels requires Podoplanin and CLEC-2 signalling via Syk, but they do not identify which CLEC-2- and Syk-expressing cell type controls lymphatic development, nor the mechanism by which they do so.
In order to investigate the role of CLEC-2 and Syk in lymphatic development Edina Schweighoffer, in Victor Tybulewicz 's lab, collaborated with Steve Watson 's group at the University of Birmingham. They analysed mice constitutively deficient in CLEC-2 and Syk throughout gestation and compared them to mice with a selective deletion of CLEC-2 and Syk in several lineages. Most significantly, they showed that loss of either CLEC-2 or Syk in the megakaryocyte/platelet lineage results in blood-filled lymphatics, as well as brain vascular defects. Further, they showed that platelets modulate the migration and intercellular adhesion of LECs through a pathway that is dependent on CLEC-2 and Syk.
These studies demonstrate that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal lymphatic development and brain vasculature, and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behaviour in vitro regulating the separation of LECs from blood vessels.
This study shows the critical role of platelet CLEC-2 and Syk in lymphangiogenesis and in the development of the brain vasculature and demonstrates that platelets directly influence LEC migration and the formation of lymphatic vessel junctions.
Victor Tybulewicz
Click image to view at full-size
Mid-gestation mouse embryos with a megakaryocyte/platelet specific deletion of Syk (top right) or CLEC-2 (Clec1b, bottom right) show oedema (asterisk), haemorrhages (blue arrow) and blood-filled lymphatics (black arrowhead). These are not seen in control embryos (left-hand side).
Original article
Brenda A Finney, Edina Schweighoffer, Leyre Navarro-Núñez, Cecile Bénézech, Francesca Barone, Craig E Hughes, Stacey A Langan, Kate L Lowe, Alice Y Pollitt, Diego Mourao-Sa, Steve Sheardown, Gerard B Nash, Nicholas Smithers, Caetano Reis e Sousa, Victor LJ Tybulewicz, Steve P Watson (2011)
CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development
Blood, Epub ahead of print. Abstract.
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