Platelet CLEC-2 and lung development.

In this article, the State of the Art lecture "Platelet CLEC-2 and Lung Development" presented at the ISTH congress 2019 is reviewed. During embryonic development, blood cells are often considered as porters of nutrition and oxygen but not as active influencers of cell differentiation. However, recent studies revealed that platelets actively facilitate cell differentiation by releasing biological substances during development. C-type lectin-like receptor 2 (CLEC-2) has been identified as a receptor for the platelet-activating snake venom rhodocytin. An endogenous ligand of CLEC-2 is the membrane protein podoplanin (PDPN), which is expressed on the surface of certain types of tumor cells and lymphatic endothelial cells (LECs). Deletion of CLEC-2 from platelets in mice results in death just after birth due to lung malformation and blood/lymphatic vessel separation. During development, lymphatic vessels are derived from cardinal veins. At this stage, platelets are activated by binding of CLEC-2 to LEC PDPN and release trandforming growth factor-β (TGF-β). This cytokine inhibits LEC migration and proliferation, facilitating blood/lymphatic vessel separation. TGF-β released upon platelet-expressed CLEC-2/LEC PDPN also facilitates differentiation of lung mesothelial cells into alveolar duct myofibroblasts (adMYFs) in the developing lung. AdMYFs generate elastic fibers inside the lung, so that the lung can be properly inflated. Thus, platelets act as an ultimate natural drug delivery system that enables biological substances to be specifically delivered to the target at high concentrations by receptor/ligand interactions during development.