Browsing by Author "Litvinov, Rustem I."

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    Combined computational modeling and experimental study of the biomechanical mechanisms of platelet-driven contraction of fibrin clots
    Michael, Christian; Pancaldi, Francesco; Britton, Samuel; Kim, Oleg V.; Peshkova, Alina D.; Vo, Khoi; Xu, Zhiliang; Litvinov, Rustem I.; Weisel, John W.; Alber, Mark (Nature Portfolio, 2023-08-24)
    While blood clot formation has been relatively well studied, little is known about the mechanisms underlying the subsequent structural and mechanical clot remodeling called contraction or retraction. Impairment of the clot contraction process is associated with both life-threatening bleeding and thrombotic conditions, such as ischemic stroke, venous thromboembolism, and others. Recently, blood clot contraction was observed to be hindered in patients with COVID-19. A three-dimensional multiscale computational model is developed and used to quantify biomechanical mechanisms of the kinetics of clot contraction driven by platelet-fibrin pulling interactions. These results provide important biological insights into contraction of platelet filopodia, the mechanically active thin protrusions of the plasma membrane, described previously as performing mostly a sensory function. The biomechanical mechanisms and modeling approach described can potentially apply to studying other systems in which cells are embedded in a filamentous network and exert forces on the extracellular matrix modulated by the substrate stiffness.
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    Megakaryocyte-induced contraction of plasma clots: Cellular mechanisms and structural mechanobiology
    Kim, Oleg V.; Litvinov, Rustem I.; Gagne, Alyssa L.; French, Deborah L.; Brass, Lawrence F.; Weisel, John W. (American Society of Hematology, 2023)
    Non-muscle cell contractility is an essential feature underlying diverse cellular processes such as motility, morphogenesis, division and genome replication, intracellular transport, and secretion. Blood clot contraction is a well-studied process driven by contracting platelets. Megakaryocytes, which are the precursors to platelets, can be found in the bone marrow and in the lungs. Although they express many of the same proteins and structures found in platelets, little is known about their ability to engage with extracellular proteins such as fibrin and contract. Here we have measured the ability of megakaryocytes to compress plasma clots. Megakaryocytes derived from human induced pluripotent stem cells (iMKs) were suspended in human platelet-free blood plasma and stimulated with thrombin. Using real-time macroscale optical tracking, confocal microscopy, and biomechanical measurements, we found that activated iMKs caused macroscopic volumetric clot shrinkage, as well as densification and stiffening of the fibrin network via fibrin-attached plasma membrane protrusions undergoing extension-retraction cycles that cause shortening and bending of fibrin fibers. Contraction induced by iMKs involved two kinetic phases with distinct rates and durations. It was suppressed by inhibitors of non-muscle myosin IIA, actin polymerization, and integrin αIIbβ3-fibrin interactions, indicating that the molecular mechanisms of iMK contractility were similar or identical to those in activated platelets. Our findings provide new insights into megakaryocyte biomechanics and suggest that iMKs can be used as a model system to study platelet contractility. Physiologically, the ability of MKs to contract plasma clots may play a role in the mechanical remodeling of intravascular blood clots and thrombi.