Journal
BLOOD
Volume 132, Issue 11, Pages 1167-1179Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-12-823369
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Funding
- KAKENHI [16K19572]
- Funding Program for Next Generation World-leading Researchers [LS052]
- Grants-in-Aid for Scientific Research [16K19572] Funding Source: KAKEN
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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 plateletactivation receptor, C-type lectin-like receptor-2 (Clec-2; encoded by Clec1b), 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, a-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 Clec1b2/2-like lung developmental abnormalities. Notably, these Clec1b2/2-like lung abnormalities were also observed after thrombocytopenia or transforming growth factor-b 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-b signaling, thus regulating normal lung development.
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