Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction
Platelets play an essential role in murine lung development through Clec-2/podoplanin interaction
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DOI：
10.1182/blood-2017-12-823369
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发表时间：
2018-09-13
期刊：
影响因子：
20.3
通讯作者：
Suzuki-Inoue, Katsue
中科院分区：
文献类型：
--
作者：
Tsukiji, Nagaharu;Inoue, Osamu;Suzuki-Inoue, Katsue
血小板不仅参与血栓形成和止血，还参与其他病理生理过程，包括肿瘤转移和炎症。然而，血小板在实体器官发育中的假定作用尚未被描述。在此，我们报道血小板通过血小板激活受体、C 型凝集素样受体 2（Clec-2；由 Clec1b 编码）及其配体、膜蛋白 podoplanin 之间的相互作用来调节肺发育。小鼠血小板中的 Clec-2 缺失会导致肺部畸形，从而导致呼吸衰竭和新生儿死亡。在这些胚胎中，初级肺泡间隔中几乎不存在α-平滑肌肌动蛋白阳性的肺泡管肌成纤维细胞（adMYF），这导致肺泡弹性纤维损失和肺畸形。我们的数据表明，adMYF 的缺乏是由肺间皮细胞（luMC）（adMYF 的主要祖细胞）的异常分化引起的。在发育中的肺中，肺泡上皮细胞 (AEC)、luMC 和淋巴内皮细胞 (LEC) 中检测到足足蛋白表达。 LEC 特异性足足蛋白敲除小鼠表现出新生儿致死性和 Clec1b2/2 样肺发育异常。值得注意的是，在胎儿血小板减少或转化生长因子-b 耗尽后也观察到这些 Clec1b2/2 样肺部异常。我们提出血小板上的 Clec-2 和 LEC 上的足足蛋白之间的相互作用通过转化生长因子-b 信号传导刺激 luMC 的 adMYF 分化，从而调节正常的肺发育。
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.