[A role of the platelet receptor CLEC-2 in lymphangiogenesis and its clinical application]

Platelets play a pivotal role in thrombosis and hemostasis; however, a series of recent research has demonstrated that platelets also play roles other than in clotting. We discovered that a platelet receptor, C-type lectin-like receptor 2 (CLEC-2), facilitates lymph/blood vessel separation in the developmental stage by binding to its ligand, podoplanin, on lymphatic endothelial cells. We have previously reported that CLEC-2-deficient mice showed blood-filled lymphatic vessels and severe edema, suggesting that CLEC-2 is essential for lymph/blood vessel separation; however, its mechanism has not been elucidated to date. Although CLEC-2 is mainly expressed in platelets and megakaryocytes, marginal expression is observed in other blood cells in mice. We found that specific deletion of CLEC-2 from platelets/megakaryocytes also impaired blood/lymphatic vessel separation, suggesting that CLEC-2 in platelets is required for separation. Based on several in vitro experiments, we proposed the mechanism of blood/lymphatic vessel separation as follows: In the developmental stage, when lymphatic vessels separate from cardinal veins, CLEC-2 in platelets binds to podoplanin in lymphatic endothelial cells. Subsequent platelet activation results in the release of platelet granule contents, including the transforming growth factor 8 family. These platelet contents inhibit migration, proliferation, and tube formation of lymphatic endothelial cells, which facilitates blood/lymphatic vessel separation. We also found that soluble CLEC-2 is released upon platelet activation. We hypothesized that plasma soluble CLEC-2 could be a marker of thrombosis and established an ELISA system to measure soluble CLEC-2. Although current tests for in vivo platelet activation require special methods for blood sampling, soluble CLEC-2 can be measured with ordinary blood sampling. We are now investigating the potential of soluble CLEC-2 as a useful marker for in vivo platelet activation.