New horizon in platelet function: with special reference to a recently-found molecule, CLEC-2.
New horizon in platelet function: with special reference to a recently-found molecule, CLEC-2.
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DOI：
10.1186/s12959-016-0099-8
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发表时间：
2016
影响因子：
3.1
通讯作者：
Suzuki-Inoue K
中科院分区：
文献类型：
--
作者：
Ozaki Y;Tamura S;Suzuki-Inoue K
血小板在止血和血栓形成的病理生理过程中起关键作用。然而，近年来越来越多地发现了血小板在血栓形成和止血之外的功能。现在存在大量证据表明，血小板在炎症、免疫、恶性肿瘤以及器官发育和再生（如肝脏）中也起着关键作用。我们最近已经确定了CLEC-2的血小板膜上，诱导细胞内激活信号的蛇毒，红细胞素的相互作用。后来我们发现，podoplanin，存在于肾足细胞和淋巴管内皮细胞，这两者都是无法接近血小板在血流中，是CLEC-2的内源性配体。与我们的预期雅阁，血小板特异性CLEC-2敲除小鼠具有水肿、淋巴管扩张和淋巴管中存在血细胞的表型。这表明，在发展阶段的淋巴管/血管分离是由血小板CLEC-2和podoplanin之间的相互作用激活的血小板释放的细胞因子存在于淋巴管内皮细胞。重组CLEC-2与早期动脉粥样硬化病变和正常动脉壁结合，与血管平滑肌细胞（VSMC）共定位。流式细胞术和免疫细胞化学显示，重组CLEC-2，但不是一个抗podoplanin抗体，结合到VSMCs，表明CLEC-2配体以外的podoplanin存在于VSMCs。使用蛋白质阵列和Biacore分析来鉴定S100 A13作为VSMC中的CLEC-2配体。S100 A13在氧化应激时释放，并在动脉粥样硬化病变的管腔区域中表达。巨核细胞生成是通过CLEC-2/podoplanin在小动脉附近的相互作用，而不是窦或淋巴管。存在表达podoplanin的骨髓（BM）小动脉基质细胞，暂称为BM成纤维网状细胞（FRC）样细胞，并且巨核细胞集落与动脉周围BM FRC样细胞共定位于BM中。CLEC-2/podoplanin相互作用诱导BM FRC样细胞分泌CCL 5以促进前血小板形成。这些观察结果表明，CLEC-2对巨核细胞和podoplanin对BM FRC样细胞之间的相互作用有助于小鼠骨髓中的动脉周围巨核微环境。
Platelets play a key role in the pathophysiological processes of hemostasis and thrombus formation. However, platelet functions beyond thrombosis and hemostasis have been increasingly identified in recent years. A large body of evidence now exists which suggests that platelets also play a key role in inflammation, immunity, malignancy, and furthermore in organ development and regeneration, such as the liver. We have recently identified CLEC-2 on the platelet membrane, which induces intracellular activation signals upon interaction of a snake venom, rhodocytin. Later we discovered that podoplanin, present in renal podocytes and lymphatic endothelial cells, both of which are not accessible to platelets in blood stream, is an endogenous ligand for CLEC-2. In accord with our expectation, platelet-specific CLEC-2 knockout mice have a phenotype of edema, lymphatic vessel dilatation, and the presence of blood cells in lymphatic vessels. It is suggested that lymphatic/blood vessel separation during the developmental stage is governed by cytokines released from platelets activated by the interaction between platelet CLEC-2 and podoplanin present on lymphatic endothelial cells. Recombinant CLEC-2 bound to early atherosclerotic lesions and normal arterial walls, co-localizing with vascular smooth muscle cells (VSMCs). Flow cytometry and immunocytochemistry showed that recombinant CLEC-2, but not an anti-podoplanin antibody, bound to VSMCs, suggesting that CLEC-2 ligands other than podoplanin are present in VSMCs. Protein arrays and Biacore analysis were used to identify S100A13 as a CLEC-2 ligand in VSMCs. S100A13 was released upon oxidative stress, and expressed in the luminal area of atherosclerotic lesions. Megakaryopoiesis is promoted through the CLEC-2/podoplanin interaction in the vicinity of arterioles, not sinusoids or lymphatic vessels. There exist podoplanin-expressing bone-marrow (BM) arteriolar stromal cells, tentatively termed as BM fibroblastic reticular cell (FRC)-like cells, and megakaryocyte colonies were co-localized with periarteriolar BM FRC-like cells in the BM. CLEC-2/podoplanin interaction induces BM FRC-like cells to secrete CCL5 to facilitate proplatelet formation. These observations indicate that a reciprocal interaction with between CLEC-2 on megakaryocytes and podoplanin on BM FRC-like cells contributes to the periarteriolar megakaryopoietic microenvironment in mouse BM.