Platelet CLEC‐2 and lung development

Abstract

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.

Targeting Podoplanin for the Treatment of Osteosarcoma

“…For the clinical development of AP201, we then performed safety tests using our previously developed human PDPN knock-in mice ( Pdpn KI/KI mice). PDPN is expressed in a broad range of normal organs and tissues, such as type I alveolar epithelial cells in the lungs and podocytes in the kidney, and is associated with development and homeostasis in some organs ( 34 ). However, we previously found that a high-dose single administration (100 mg/kg) of 2F7 surrogate anti-monkey PDPN antibody harboring PG4D2-like neutralizing activity did not demonstrate acute toxicity in cynomolgus monkeys ( 33 ).…”

Identification of angiogenesis‐related genes signature for predicting survival and its regulatory network in glioblastoma

“…It has been revealed that PDPN expression level is upregulated by TGF‐β in other cancer types. 45 , 46 The binding of PDPN and its receptor, C‐type lectin‐like receptor 2 (CLEC‐2), specifically distributed on platelet/megakaryocytes in human, activates platelet to release cytokines including TGF‐β, 47 , 48 thus facilitating angiogenesis and EMT. Consequently, aforementioned mechanism may inspire the exploration of regulatory significance of PDPN in GBM.…”

Platelet-Rich Plasma in Dermatology: New Insights on the Cellular Mechanism of Skin Repair and Regeneration

“…Through this, they can bind podoplanin (a type I transmembrane sialomucin-like glycoprotein), which can lead to platelet activation, but the deficiency of podoplanin impairs lymphatic vessel formation [206,207]. Platelets are also involved in the embryonic differential development of lymph vessels and blood vessels, while also maintaining this separation (e.g., by platelets' plugs), or being involved in further lymphatic vessel-repairing processes [208][209][210].…”