Platelet mechanosensing of substrate stiffness during clot formation mediates adhesion, spreading, and activation

• Type of Material: Article
• Authors: Yongzhi Qiu, Emory University; Ashley C. Brown, Georgia Institute of Technology; David R Myers, Emory University; Yumiko Sakurai, Georgia Institute of Technology; Robert G. Mannino, Georgia Institute of Technology; Reginald Tran, Emory University; Byungwook Ahn, Georgia Institute of Technology; Elaissa Hardy, Emory University; Matthew F. Kee, Georgia Institute of Technology; Sanjay Kumar, University of California Berkeley; Gang Bao, Emory University; Thomas Barker, Emory University; Wilbur Lam, Emory University
• Language: English
• Date: 2014-10-07
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2020 National Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1322917111
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 111
• Issue: 40
• Start Page: 14430
• End Page: 14435
• Grant/Funding Information: Finanical support for this work was provided by National Science Foundation CAREER Award 1150235 (to W.A.L.); National Science Foundation Grant CBET-0939511 (to G.B.); an American Heart Association Innovative Research Grant (to W.A.L.); National Institutes of Health Grants U54HL112309 (to W.A.L.), R01HL121264 (to W.A.L.), and PN2EY018244 (to G.B. and W.A.L.); and American Heart Association Postdoctoral Fellowships (to A.C.B. and D.R.M.).
• Keywords: CELLS; biomaterials; Science & Technology - Other Topics; FIBRIN; P-SELECTIN; RIGIDITY; Science & Technology; Multidisciplinary Sciences; platelet cytoskeleton; THROMBUS FORMATION; LIGAND DENSITY; STABILITY; GRANULE SECRETION; mechanotransduction; CYTOSKELETON; SHEAR-STRESS; cell mechanics
• Research Categories: Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

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 anudeate 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 α11bβ3 activation, α-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.