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Blood. 2018 Sep 13;132(11):1167-1179. doi: 10.1182/blood-2017-12-823369. Epub 2018 May 31.

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

Author information

1
Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
2
Infection Control Office, Yamanashi University Hospital, Chuo, Yamanashi, Japan.
3
Laboratory for Lung Development, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan.
4
Department of Anatomy, The Jikei University School of Medicine, Tokyo, Japan.
5
Advanced Biotechnology Center, University of Yamanashi, Chuo, Yamanashi, Japan.
6
Division of Vascular Biology, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kofu, Yamanashi, Japan; and.
7
Division of Molecular Cell Biology, Core Research Facilities for Basic Science, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan.

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 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, 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 Clec1b-/--like lung developmental abnormalities. Notably, these Clec1b-/--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.

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