Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction

Abstract

Platelets participate in not only thrombosis and hemostasis but also other pathophysiological processes, including tumor metastasis and inflammation. However, the putative role of platelets in the development of solid organs has not yet been described. Here, we report that platelets regulate lung development through the interaction between the platelet-activation receptor, C-type lectin-like receptor-2 (Clec-2; encoded by ), and its ligand, podoplanin, a membrane protein. Clec-2 deletion in mouse platelets led to lung malformation, which caused respiratory failure and neonatal lethality. In these embryos, α-smooth muscle actin-positive alveolar duct myofibroblasts (adMYFs) were almost absent in the primary alveolar septa, which resulted in loss of alveolar elastic fibers and lung malformation. Our data suggest that the lack of adMYFs is caused by abnormal differentiation of lung mesothelial cells (luMCs), the major progenitor of adMYFs. In the developing lung, podoplanin expression is detected in alveolar epithelial cells (AECs), luMCs, and lymphatic endothelial cells (LECs). LEC-specific podoplanin knockout mice showed neonatal lethality and-like lung developmental abnormalities. Notably, these -like lung abnormalities were also observed after thrombocytopenia or transforming growth factor-β depletion in fetuses. We propose that the interaction between Clec-2 on platelets and podoplanin on LECs stimulates adMYF differentiation of luMCs through transforming growth factor-β signaling, thus regulating normal lung development.

Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

“…Recently, it was demonstrated that the interaction between platelet CLEC-2 receptor and lymphatic endothelial cell podoplanin regulates murine lung development. This direct interaction leads through platelet activation to TGF-␤1 release, which is necessary for normal lung cell differentiation during late embryonic development (44). Our in vitro data provide additional evidence of CLEC-2-mediated TGF-␤1 release from platelets.…”

Severe but not moderate hyperoxia of newborn mice causes an emphysematous lung phenotype in adulthood without persisting oxidative stress and inflammation

“…Moreover, the blood cell count of adult mice treated with moderate neonatal hyperoxia differed from untreated mice with particular increase in platelets. Murine platelets are mainly generated from megakaryocytes in the lung tissue [48] and are able to support the lung development [49]. Therefore, its increase could suggest higher activity of cellular processes compensating for the oxygen-mediated damages, but the potential role of platelets in the reduction of oxygen-mediated damages in newborn lungs is still unknown.…”

Functional significance of the platelet immune receptors GPVI and CLEC-2

“…ner (56). The degree of blood-lymphatic mixing is reduced in mice with a targeted deletion of CLEC-2 in the megakaryocyte/platelet lineage (PF4-Cre.Clec-1b fl/fl ), and the mice are viable, albeit with a 30% reduction in platelet count.…”