Platelet integrins exhibit anisotropic mechanosensing and harness piconewton forces to mediate platelet aggregation
Platelet integrins exhibit anisotropic mechanosensing and harness piconewton forces to mediate platelet aggregation
复制标题
DOI：
10.1073/pnas.1710828115
复制
发表时间：
2018-01-09
影响因子：
11.1
通讯作者：
Salaita, Khalid
中科院分区：
文献类型：
--
作者：
Zhang, Yun;Qiu, Yongzhi;Salaita, Khalid
血管损伤部位的血小板聚集在凝血过程中是必不可少的。在此过程中，血小板被结合表面整合素受体的可溶性纤维蛋白原桥接。血小板聚集机制中的一个谜团是，静息血小板如何忽略可溶性纤维蛋白原（血流中第三丰富的蛋白质），而在原发性损伤部位，却贪婪地将固定的纤维蛋白原结合在其他血小板表面。我们推测，血小板整合素是机械传感器，测试其配体通过血小板-血小板突触。为了研究这个模型，我们询问人类血小板使用的方法，包括支持的脂质双层平台以及DNA张力传感器技术。实验表明，血小板整合素需要侧向力来介导血小板-血小板相互作用。机械不稳定的配体抑制血小板活化，并且皮牛顿整联蛋白张力的开始与钙通量一致。活化的血小板在其表面显示固定的纤维蛋白原，从而介导静息血小板的进一步募集。整合素张力的分布被证明是通过两个肌球蛋白信号通路，肌球蛋白轻链激酶和Rho相关激酶空间调节。最后，我们发现整合素张力的终止与磷脂酰丝氨酸的暴露相结合。我们的工作揭示了最高的空间和时间分辨率地图的血小板整合素力学及其在血小板聚集中的作用，这表明，血小板是物理基板彼此建立机械反馈回路的激活。这些结果让人想起T细胞受体、E-钙粘蛋白和Notch通路的机械调节，表明细胞连接处信号传导的共同特征。
Platelet aggregation at the site of vascular injury is essential in clotting. During this process, platelets are bridged by soluble fibrinogen that binds surface integrin receptors. One mystery in the mechanism of platelet aggregation pertains to how resting platelets ignore soluble fibrinogen, the third most abundant protein in the bloodstream, and yet avidly bind immobile fibrinogen on the surface of other platelets at the primary injury site. We speculate that platelet integrins are mechanosensors that test their ligands across the platelet-platelet synapse. To investigate this model, we interrogate human platelets using approaches that include the supported lipid bilayer platform as well as DNA tension sensor technologies. Experiments suggest that platelet integrins require lateral forces to mediate platelet-platelet interactions. Mechanically labile ligands dampen platelet activation, and the onset of piconewton integrin tension coincides with calcium flux. Activated platelets display immobilized fibrinogen on their surface, thus mediating further recruitment of resting platelets. The distribution of integrin tension was shown to be spatially regulated through two myosin-signaling pathways, myosin light chain kinase and Rho-associated kinase. Finally, we discovered that the termination of integrin tension is coupled with the exposure of phosphatidylserine. Our work reveals the highest spatial and temporal resolution maps of platelet integrin mechanics and its role in platelet aggregation, suggesting that platelets are physical substrates for one another that establish mechanical feedback loops of activation. The results are reminiscent of mechanical regulation of the T-cell receptor, E-cadherin, and Notch pathways, suggesting a common feature for signaling at cell junctions.