Platelet lamellipodium formation is not required for thrombus formation and stability

Schurr, Yvonne; Sperr, A.; Volz, Joachim; Beck, Sarah; Reil, Lucy; Kusch, Charly; Eiring, Patrick; Bryson, Sheila; Sauer, Markus; Nieswandt, Bernhard; Machesky, Laura M.; Bender, Markus

doi:10.1182/blood.2019002105

Cited by 41 publications

(62 citation statements)

References 40 publications

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“…6b) and adherent platelets formed prominent filopodia (Fig. 6b), confirming previous observations 31 . Time-lapse video microscopy, however, revealed premature lamellipodia-like extensions that protrude and retract between adjacent filopodia, but do not extend to filopodial tips (Supplementary Movie 6); and mean projected platelet area was significantly larger compared to Arpc2−/− platelets ( Fig.…”

Section: Resultssupporting

confidence: 91%

“…6a). Previous reports have shown that WAVE rather than WASp is required for lamellipodia formation in platelets 31,44 . Indeed, spreading area of platelets isolated from conditional Pf4cre+/− Cyfip1fl/fl (Cyfip1−/−) mice was largely reduced compared to controls ( Fig.…”

Section: Resultsmentioning

confidence: 91%

“…1e and Supplementary Fig. 1h) 30,31 . Unlike the two-dimensional (2D) fibrin(ogen) patches deposited at the inflamed vessel wall, fibrin(ogen) in the core of thrombotic lesions formed a three-dimensional (3D) meshwork fully imbedding platelets ( Fig.…”

Section: Resultsmentioning

confidence: 97%

“…The Arp2/3 complex of platelets is activated by nucleation-promoting factors (NPFs) of the Wiskott–Aldrich syndrome protein (WASp) and WASp-family verprolin-homologous protein (WAVE) families 17 , 26 . To test the contribution of these NPFs in platelet migration and haptotaxis, we analyzed platelets deficient in WASp or Cyfip1, the Rac1-binding subunit of the WAVE complex required for its activation in platelets 31 . WASp−/− platelets formed lamellipodia similar to control platelets and showed unimpaired migration and fibrinogen removal, indicating a redundant role of WASp in lamellipodia formation and platelet migration (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Vascular surveillance by haptotactic blood platelets in inflammation and infection

et al. 2020

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Breakdown of vascular barriers is a major complication of inflammatory diseases. Anucleate platelets form blood-clots during thrombosis, but also play a crucial role in inflammation. While spatio-temporal dynamics of clot formation are well characterized, the cell-biological mechanisms of platelet recruitment to inflammatory micro-environments remain incompletely understood. Here we identify Arp2/3-dependent lamellipodia formation as a prominent morphological feature of immune-responsive platelets. Platelets use lamellipodia to scan for fibrin(ogen) deposited on the inflamed vasculature and to directionally spread, to polarize and to govern haptotactic migration along gradients of the adhesive ligand. Platelet-specific abrogation of Arp2/3 interferes with haptotactic repositioning of platelets to microlesions, thus impairing vascular sealing and provoking inflammatory microbleeding. During infection, haptotaxis promotes capture of bacteria and prevents hematogenic dissemination, rendering platelets gate-keepers of the inflamed microvasculature. Consequently, these findings identify haptotaxis as a key effector function of immune-responsive platelets.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

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Vascular surveillance by haptotactic blood platelets in inflammation and infection

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“…This was surprising, but we cannot exclude at present that-as opposed to DCs or macrophagesplatelets might be capable of expressing low amounts of the mostly non-hematopoietic Hem1 orthologue Nap1, allowing for WRC-driven Arp2/3 complex activation in a fashion indistinguishable from Hem1. Interestingly, platelets conditionally deleted for Cyfip1 but still harboring the intact gene for Cyfip2 display related but less severe phenotypes with aberrant morphology and reduced activatability (89), potentially due to residual WRC function. Likewise, when generating mouse melanoma cells CRISPR/Cas9-edited for Nap1, we isolated clones with differential but low levels of compensatory Hem1-expression, giving rise to significant levels of lamellipodia formation (48).…”

Section: Fc Gamma Receptor (Fc R)-induced Phagocytosis Is Mainly Accomentioning

confidence: 99%

Loss of Hem1 disrupts macrophage function and impacts on migration, phagocytosis and integrin-mediated adhesion

Stahnke

Döring

Kusch

et al. 2020

Preprint

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# equal contribution One sentence summaryInterference of Hem1 function in mice and cells uncovers a hitherto unrecognized role in integrinmediated cell adhesion that is crucial for macrophage function and connects to recently discovered immunodeficiencies in patients carrying Hem1 mutations. ABSTRACTThe hematopoietic-specific protein 1 (Hem1) comprises an essential subunit of the WAVE Regulatory Complex (WRC) in immune cells. WRC has a fundamental role in Arp2/3 complex activation and the protrusion of branched actin networks in motile cells.Hem1 deficiency leads to suppression of the entire WRC in immune cells. Defective WRC function in macrophages results in loss of lamellipodia and migration defects. Moreover, phagocytosis, commonly accompanied by lamellipodium protrusion during cup formation, is altered in Hem1 null cells concerning frequency and efficacy. When analyzing cell spreading, adhesion and podosome formation, we found that Hem1 null cells are capable, in principle, of podosome formation and consequently, do not show any quantitative differences in extracellular matrix degradation. Their adhesive behavior, however, was significantly altered. Specifically, adhesion as well as de-adhesion of Hem1 null cells was strongly compromised, likely contributing to the observed reduced efficiency of phagocytosis. In line with this, phosphorylation of the prominent adhesion component paxillin was diminished. Nonhematopoietic somatic cells disrupted in expression for both Hem1 and its ubiquitous orthologue Nckassociated protein 1 (Nap1) or the essential WRC components Sra-1/PIR121 did not only confirm defective paxillin phosphorylation, but also revealed that paxillin turnover in focal adhesions is accelerated in the absence of WRC. Finally, adhesion assays using platelets lacking functional WRC as model system unmasked radically decreased IIb 3 integrin activation.Our results thus demonstrate that WRC-driven actin networks impact on integrin-dependent processes controlling formation and dismantling of different types of cell-substratum adhesion.Cell migration follows an orchestrated sequence of events, a cycle of cell protrusion, adhesion to newly occupied space and contraction to drag the cell body forward. Polymerization of actin filaments (Factin) at the cell front pushes the plasma membrane into the direction of migration, which then attaches to the extracellular substratum via members of the integrin transmembrane receptors family.Cells in metazoan organisms are capable of migrating through complex, 3-dimensional environments and their license keys to different organismal compartments constitute combinations of integrins they carry on their surface, allowing them to specifically adhere to given substrata (1, 2). Once engaged, the integrins dynamically couple to the actin cytoskeleton, which in turn can exert pulling forces through myosin II activation and contraction, culminating in locomotion of the cell body (3-5)Integrins are heterodimeric cell surface receptors that are responsible for cell adhesion duri...

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Illustrated State‐of‐the‐Art Capsules of the ISTH 2020 Congress

Ariëns

Becattini

Bender³

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12‐15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists. Presenters are asked to create Illustrated Capsules of their talks, which are concise illustrations with minimal explanatory text. Capsules cover major themes of the presentation, and these undergo formal peer review for inclusion in this article. Owing to the shift to a virtual congress this year, organizers reduced the program size. There were 39 SOA lectures virtually presented, and 29 capsules (9 from talks omitted from the virtual congress) were both submitted and successful in peer review, and are included in this article. Topics include the roles of the hemostatic system in inflammation, infection, immunity, and cancer, platelet function and signaling, platelet function disorders, megakaryocyte biology, hemophilia including gene therapy, phenotype tests in hemostasis, von Willebrand factor, anticoagulant factor V, computational driven discovery, endothelium, clinical and basic aspects of thrombotic microangiopathies, fibrinolysis and thrombolysis, antithrombotics in pediatrics, direct oral anticoagulant management, and thrombosis and hemostasis in pregnancy. Capsule authors invite virtual congress attendees to refer to these capsules during the live presentations and participate on Twitter in discussion. Research and Practice in Haemostasis and Thrombosis will release 2 tweets from @RPTHJournal during each presentation, using #IllustratedReview, #CoagCapsule and #ISTH2020. Readers are also welcome to utilize capsules for teaching and ongoing education.

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Platelet lamellipodium formation is not required for thrombus formation and stability

Abstract: Key Points Cyfip1 plays a crucial role for branching of actin filaments and for lamellipodium formation. Lamellipodium formation is not required for the formation of a hemostatic plug or thrombus.

Cited by 41 publications

References 40 publications

Vascular surveillance by haptotactic blood platelets in inflammation and infection

Vascular surveillance by haptotactic blood platelets in inflammation and infection

Loss of Hem1 disrupts macrophage function and impacts on migration, phagocytosis and integrin-mediated adhesion

Illustrated State‐of‐the‐Art Capsules of the ISTH 2020 Congress

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