Skip to main content
ISTH 2024 Main banner
Back

Poster Networking

Platelets and Megakaryocytes

PB0754 - MICAL1, a new actor in platelets, governing shear-dependent adhesive and thrombotic functions of platelets via actin regulation within the GPIb complex.

Monday, June 24, 2024
13:45 – 14:45 ICT
Room: Exhibition Hall

    Presenting Author(s)

  • Jean Solarz

    Phd student
    INSERM U1176, Université Paris Saclay, Le Kremlin-Bicêtre, France
    Le Kremlin-Bicêtre, Ile-de-France, France

    • Co-Author(s)

  • CS

    Christelle Soukaseum

    Research engineer
    INSERM U1176, Université Paris Saclay, Le Kremlin-Bicêtre, France
    Le Kremlin-Bicêtre, Ile-de-France, France

  • CR

    Christelle Repérant

    Assistant engineer
    INSERM U1176, Université Paris Saclay, Le Kremlin-Bicêtre, France
    Le Kremlin-Bicêtre, Ile-de-France, France

  • SF

    Stéphane Frémont

    Researcher
    Institut Pasteur, Université Paris Cité, CNRS UMR3691, Paris, France
    Paris, Ile-de-France, France

  • TS

    Thibaud Séfiane

    Phd Student
    INSERM U1176, Université Paris Saclay, Le Kremlin-Bicêtre, France
    Le Kremlin-Bicêtre, Ile-de-France, France

  • VP

    Valérie Proulle

    MD, Researcher
    INSERM U1138, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France ; Service d'Hématologie Biologique et Unité Fonctionnelle d'Hémostase, Hôpital Cochin, AP-HP Centre, Université Paris Cité, Paris, France
    Paris, Ile-de-France, France

  • ER

    Elisa Rossi

    Researcher
    INSERM U1140, Université Paris Cité, Paris, France
    Paris, Ile-de-France, France

  • JB

    Jean-Claude Bordet

    Researcher
    UR4609 Hémostase & Thrombose, Université Claude Bernard Lyon, Lyon, France
    Lyon, Rhone-Alpes, France

  • Cécile V. Denis

    Researcher
    INSERM U1176, Université Paris Saclay, Le Kremlin-Bicêtre, France
    Le Kremlin-Bicêtre, Ile-de-France, France

  • DB

    Dominique Baruch

    Researcher
    INSERM U1140, Université Paris Cité, Paris, France
    Paris, Ile-de-France, France

  • PM

    Pierre H. Mangin, PhD

    Researcher
    University of Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, Strasbourg, France
    Strasbourg, Alsace, France

  • YB

    Yacine Boulaftali

    Researcher
    INSERM U1148, Université Paris Cité, Paris, France
    Paris, Ile-de-France, France

  • RP

    R. Jeroen Pasterkamp

    Researcher
    Department of Translational Neuroscience, University Medical Center Utrecht, Brain Center, Utrecht University, Utrecht, The Netherlands
    Utrecht, Utrecht, Netherlands

  • HR

    Hana Raslova

    Researcher
    INSERM U1287, Gustave Roussy, Université Paris Saclay, Villejuif, France
    Villejuif, Ile-de-France, France

  • AE

    Arnaud Echard

    Researcher
    Institut Pasteur, Université Paris Cité, CNRS UMR3691, Paris, France
    Paris, Ile-de-France, France

  • FA

    Frédéric Adam

    Researcher
    INSERM U1176, Université Paris Saclay, Le Kremlin-Bicêtre, France
    Le Kremlin-Bicêtre, Ile-de-France, France

  • Alexandre KAUSKOT, PhD

    Researcher INSERM
    INSERM U1176, Hôpital Bicêtre
    Le Kremlin-Bicêtre, Ile-de-France, France

Background: MICAL1 promotes depolymerization of F-actin by mediating oxidation of specific methionine residues resulting in actin filament disassembly

Aims: To understand how MICAL1-dependent actin regulation intervenes in platelet function.

Methods: Tissue-specific knockout mice lacking Mical1 in platelet lineage: wild-type Mical1fl/fl (Mical1+/+) and knock-out Mical1fl/fl;Pf4Cre (Mical1−/−).

Results: In a tail clip assay, Mical1−/− mice exhibited a slightly significant increase in bleeding time compared to Mical1+/+ mice, and in a FeCl3-induced thrombosis model, the arterial occlusion time was significantly prolonged in Mical1−/− mice (p < 0.001) and associated with unstable thrombi leading to occlusion by embolization.
Flow chamber assays on von Willebrand factor (vWF) matrix showed a 30% reduction in platelet adhesion (at 1,500s-1) and stability (at 9,000s-1) in Mical1−/− compared to Mical1+/+ platelets. Adherent Mical1−/− platelets exhibited increased F-actin content. Treatment of Mical1+/+ platelets with the F-actin stabilization drug Jasplakinolide mirrored the deficiency of MICAL1, by dramatically inhibiting adhesion and stability. Abnormal F-actin polymerization in Mical1−/− platelets was demonstrated by a very low Latrunculin-A concentration, an F-actin depolymerizing drug, rescuing platelet adhesion and stability in Mical1−/− mice. Mical1−/− platelets adhered normally to vWF in static and to fibrinogen in static and flow assays, suggesting a specific role of MICAL1 in a shear-dependent manner, possibly through the vWF mechanoreceptor glycoprotein (GP)Ib. Immunoprecipitation experiments revealed the association of MICAL1 with GPIb during platelet stimulation by vWF in a polymerized F-actin-dependent manner. Importantly, an increase in GPIbα-associated actin in Mical1−/− platelets under shear altered GPIb-vWF signaling and increased velocity (p < 0.01), which was rescued upon Latrunculin-A treatment.

Conclusion(s): Our findings highlight MICAL1 as a new pivotal actor in controlling platelet interactions between vWF and GPIb, ensuring correct platelet adhesion, and stability under flow through F-actin regulation within the GPIb receptor.