The role of fibrinogen spacing and patch size on platelet adhesion under flow

Walle, Aurore Van de; Fontenot, Jeffrey; Spain, Travis G.; Brunski, Daniel B.; Sanchez, Ernest S.; Keay, Joel C.; Curtis, Mark E.; Johnson, Matthew B.; Snyder, Trevor A.; Schmidtke, David W.

doi:10.1016/j.actbio.2012.07.013

Cited by 15 publications

(18 citation statements)

References 30 publications

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“…The effect of P-selectin presentation length on the extent of monocyte rolling adhesion demonstrated in our experiments parallels findings by others regarding length scale-regulated effects on platelet adhesion to fibrinogen 41 and leukocyte adhesion to P-selectin 30 . Yet, to our knowledge, this is the first report to detail how a two-step adhesion process (rolling and firm adhesion) under hemodynamic conditions is regulated by the geometry of lumen-presented cell adhesion proteins.…”

Section: Discussionsupporting

confidence: 90%

“…In order to do so, the instantaneous rolling velocity as well as the time and length over which a cell mediates rolling adhesion contact with a substrate (Fig. S5), qualities of rolling adhesion, which may in turn influence the ability of cells to firmly adhere 31, 41 , were quantified. While instantaneous rolling velocity of THP-1 cells rolling on P-selectin-only functionalized stripes did not appreciably vary with stripe length, on average, higher P-selectin concentrations facilitated lower rolling adhesion velocities (Fig.…”

Section: Resultsmentioning

confidence: 99%

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P-Selectin and ICAM-1 synergy in mediating THP-1 monocyte adhesion in hemodynamic flow is length dependent

Edwards

Thomas

2017

Integr. Biol.

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The tightly orchestrated recruitment of monocytes, whose progeny are critical to the progression and resolution of various physiological and pathophysiological processes, is implicated in the time course, severity, and resolution of pathology. Using a microfluidic-based cell adhesion assay integrating spatiotemporal analyses and micropatterning of adhesive proteins, we interrogated the effects of adhesive molecule presentation length, which varies in vivo with disease and stage, on THP-1 monocyte cell rolling versus firm adhesion mediated by P-selectin and/or ICAM-1 in hemodynamic flow. Our results indicate that co-presentation of P-selectin and ICAM-1 substantially decreases the length of adhesive substrate required to sustain adhesion in flow and that P-selectin functions synergistically with ICAM-1 to substantially enhance THP-1 firm adhesion. This synergy was found to furthermore correlate with diminished cell rolling velocities and length-enhanced secondary cell capture. Our results suggest pathophysiological ramifications for local remodeling of the inflamed microvascular microenvironment in directing the efficiency of monocyte trafficking.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

P-Selectin and ICAM-1 synergy in mediating THP-1 monocyte adhesion in hemodynamic flow is length dependent

Edwards

Thomas

2017

Integr. Biol.

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“…[20][21][22][23] In this work, we apply microcontact printing to create micro/nanoscale patterns of matrix proteins that mediate platelet adhesion and activation, to demonstrate that the microenvironmental geometry directly mediates platelet physiology and function. Specifically, we demonstrate that platelet a-granule secretion is spatially regulated at the micro/nanoscale via rearrangement of the actin cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

Platelet geometry sensing spatially regulates α-granule secretion to enable matrix self-deposition

Sakurai

Fitch-Tewfik

Qiu

et al. 2015

Blood

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• The geometric orientation of the underlying matrix regulates platelet a-granule secretion.• On geometrically constrained matrices, platelets selfdeposit additional matrix, providing more cell membrane to extend spreading.Although the biology of platelet adhesion on subendothelial matrix after vascular injury is well characterized, how the matrix biophysical properties affect platelet physiology is unknown. Here we demonstrate that geometric orientation of the matrix itself regulates platelet a-granule secretion, a key component of platelet activation. Using protein microcontact printing, we show that platelets spread beyond the geometric constraints of fibrinogen or collagen micropatterns with <5-mm features. Interestingly, a-granule exocytosis and deposition of the a-granule contents such as fibrinogen and fibronectin were primarily observed in those areas of platelet extension beyond the matrix protein micropatterns. This enables platelets to "self-deposit" additional matrix, provide more cellular membrane to extend spreading, and reinforce platelet-platelet connections. Mechanistically, this phenomenon is mediated by actin polymerization, Rac1 activation, and a IIb b 3 integrin redistribution and activation, and is attenuated in gray platelet syndrome platelets, which lack a-granules, and Wiskott-Aldrich syndrome platelets, which have cytoskeletal defects. Overall, these studies demonstrate how platelets transduce geometric cues of the underlying matrix geometry into intracellular signals to extend spreading, which endows platelets spatial flexibility when spreading onto small sites of exposed subendothelium. (Blood. 2015;126(4):531-538) IntroductionHemostasis begins with platelet adhesion and activation at the site of vascular injury.1 Platelets then secrete their a-and dense granules, leading to further recruitment of other platelets and the formation of a hemostatic plug.2 Extensive research has characterized the underlying biological signaling pathways that govern these processes at the bulk level via in vivo and in vitro techniques.3 However, how platelets interact with their microenvironment at the single-cell level and how these interactions subsequently influence platelet physiology remain poorly understood. For example, although single platelets have long been observed to fill submicron-sized "gaps" in the endothelium, 4 how platelets establish adhesion on such small areas of exposed matrix that is strong enough to withstand the shear forces of the circulation is unknown. Studies of single platelet-matrix interactions may help explain the role of platelets in maintaining vascular integrity and supporting the semipermeable barrier function of the endothelium during homeostatic conditions. 5 Furthermore, because platelets within different regions of the same thrombus exhibit significantly different levels of activation, 6,7 this concept of physical and microenvironmental regulation of platelet physiology at the single-cell level is also important for our overall understanding of clot formation. S...

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“…When length of patterns was decreased in the downstream direction to < 6µm, platelet adhesion was significantly decreased. αIIbβ3 integrin binding to fibrinogen was confirmed to be the cause of platelet aggregation in this system, as adhesion did not occur in the presence of a blocking antibody [60]. …”

Section: Platelet Mechanics and The Ecm Microenvironmentmentioning

confidence: 99%

The Platelet and the Biophysical Microenvironment: Lessons from Cellular Mechanics

Ciciliano

Tran

Sakurai

et al. 2014

Thrombosis Research

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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.

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The role of fibrinogen spacing and patch size on platelet adhesion under flow

Cited by 15 publications

References 30 publications

P-Selectin and ICAM-1 synergy in mediating THP-1 monocyte adhesion in hemodynamic flow is length dependent

P-Selectin and ICAM-1 synergy in mediating THP-1 monocyte adhesion in hemodynamic flow is length dependent

Platelet geometry sensing spatially regulates α-granule secretion to enable matrix self-deposition

The Platelet and the Biophysical Microenvironment: Lessons from Cellular Mechanics

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