The Platelet and the Biophysical Microenvironment: Lessons from Cellular Mechanics

Abstract

While the role of platelets in hemostasis is well characterized from a biological perspective, the biophysical interactions between platelets and their mechanical microenvironment are relatively unstudied. The field of cellular mechanics has developed a number of approaches to study the effects of extracellular matrix (ECM)-derived mechanical forces on various cells, and has elucidated that integrin-cytoskeleton-mediated force transduction governs many cellular processes. As platelets adhere and spread via similar molecular machinery that enables other cells to mechanosense and mechanotransduce forces from their biophysical microenvironment, platelets too are likely governed by the same overarching mechanisms. Indeed, recent platelet mechanobiology studies have revealed that key aspects of platelet physiology and activation are regulated by the mechanical and spatial properties of the ECM microenvironment. At the same time, there are also key differences that make platelets unique in the world of cells-- their size, origin as megakaryocyte fragments, unique αIIbβ3 integrin-- render their mechanosensing activities particularly interesting. The structurally “simple,” anucleate nature of platelets coupled with their high actin concentration (20% of total protein) and integrin density [1] seem to make them ideal for mechanical force generation and transmission. Further studies will enhance our understanding of the role of platelet mechanobiology in hemostasis and thrombosis, potentially leading to new categories of diagnostics that investigate the mechanical properties of clots to determine bleeding risk, as well as therapies that target the mechanotransduction signaling pathway to alter the stability of clots.

Rupture Forces among Human Blood Platelets at different Degrees of Activation

“…However, these processes are not well understood as platelets are difficult to handle because they activate immediately after short contact with non-physiological surfaces 16 17 18 , at elevated shear stress 19 and upon air contact 20 . Among these, platelet activation on surfaces is not only a major drawback for microfluidic devices 21 , micro- and nano- particulate drug delivery systems 22 23 , and intravascular devices 24 , but it is also essential for developing tools for direct measuring of platelet mechanics 25 26 .…”

Platelet Shape Changes during Thrombus Formation: Role of Actin-Based Protrusions

“…have been applied in platelet biology, the reader is referred to Ciciliano et al, 24 Feghhi et al, 25 and to the recent reviews from Zaninetti et al 26 and Sachs et al 27…”

Role of Platelet Cytoskeleton in Platelet Biomechanics: Current and Emerging Methodologies and Their Potential Relevance for the Investigation of Inherited Platelet Disorders

“…The structural connectors between actin cytoskeleton and intracellular portions of integrins (e.g., β tail of GP IIb/IIIa) are diverse proteins such as filamin, myosin, and actinin-α-1. 14,34 Moreover, upon platelet activation, cytoskeleton microtubules disassemble, which maintains the discoid platelet shape in nonactivated platelets, and actin filaments assemble. [35][36][37] Actin-myosin interactions, supported by the microtubule architecture, drive platelet centripetal contraction and ensure the maintenance of platelet structure during spreading.…”

“…Biomechanical properties of platelets, which are mainly contributed by the cytoskeleton, are increasingly recognized as highly relevant for platelet function. 34,43 Alterations in biomechanical properties resulting in changes in contractility during adhesion-mediated spreading and intrinsic viscoelastic properties governing platelet deformation can potentially serve as label-free diagnostic markers of a pathophysiological state of blood platelets. 44,45 A wide variety of biophysical techniques are currently used to assess cytoskeleton-dependent contractile force generation at piconewton (pN) and biomechanical properties of platelets at nanometer (nm) regimes.…”