Platelet mechanosensing of substrate stiffness during clot formation mediates adhesion, spreading, and activation
Platelet mechanosensing of substrate stiffness during clot formation mediates adhesion, spreading, and activation
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DOI：
10.1073/pnas.1322917111
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发表时间：
2014-10-07
影响因子：
11.1
通讯作者：
Lam, Wilbur A.
中科院分区：
文献类型：
--
作者：
Qiu, Yongzhi;Brown, Ashley C.;Lam, Wilbur A.
当血小板在血管损伤部位聚集和激活以阻止出血时，它们会受到无数的生化和生物物理信号和信号的影响。随着血栓的形成，血小板与聚合的纤维蛋白支架相互作用，使血小板暴露在广泛的机械微环境中。在这里，我们首次(据我们所知)表明，作为无核细胞碎片的血小板，可以感知微环境机械特性，如底物硬度，并将这些信号转化为不同的生物信号。具体地说，当血小板机械感应基础纤维蛋白/纤维蛋白原底物的硬度时，增加底物硬度会导致血小板黏附和铺展的增加。重要的是，黏附在更坚硬的基质上也会导致更高水平的血小板激活，如整合素α(IIb)β(3)激活、α-颗粒分泌和促凝活性。从机制上讲，我们确定了rac1和肌动球蛋白活性在不同程度上介导了底物刚性依赖的血小板黏附、铺展和激活。血小板能够机械感知血栓或止血栓中的微环境信号，然后将这些信号机械转换为不同水平的血小板黏附、扩散和激活，这为我们提供了对血栓形成过程中血小板聚集和血小板激活异质性的潜在机制的生物物理见解。
As platelets aggregate and activate at the site of vascular injury to stem bleeding, they are subjected to a myriad of biochemical and biophysical signals and cues. As clot formation ensues, platelets interact with polymerizing fibrin scaffolds, exposing platelets to a large range of mechanical microenvironments. Here, we show for the first time (to our knowledge) that platelets, which are anucleate cellular fragments, sense microenvironmental mechanical properties, such as substrate stiffness, and transduce those cues into differential biological signals. Specifically, as platelets mechanosense the stiffness of the underlying fibrin/fibrinogen substrate, increasing substrate stiffness leads to increased platelet adhesion and spreading. Importantly, adhesion on stiffer substrates also leads to higher levels of platelet activation, as measured by integrin alpha(IIb)beta(3) activation, a-granule secretion, and procoagulant activity. Mechanistically, we determined that Rac1 and actomyosin activity mediate substrate stiffness-dependent platelet adhesion, spreading, and activation to different degrees. This capability of platelets to mechanosense microenvironmental cues in a growing thrombus or hemostatic plug and then mechanotransduce those cues into differential levels of platelet adhesion, spreading, and activation provides biophysical insight into the underlying mechanisms of platelet aggregation and platelet activation heterogeneity during thrombus formation.