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Megakaryocyte-induced contraction of plasma clots: cellular mechanisms and structural mechanobiology.

  • Kim, Oleg V1, 2
  • Litvinov, Rustem I1
  • Gagne, Alyssa L3
  • French, Deborah L4
  • Brass, Lawrence F5
  • Weisel, John W1
  • 1 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 2 Department of Biomedical Engineering and Mechanics, Fralin Biomedical Research Institute, Center for Soft Matter and Biological Physics, Virginia Tech, Blacksburg, VA.
  • 3 Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA.
  • 4 Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA.
  • 5 Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Published Article
American Society of Hematology
Publication Date
Feb 08, 2024
DOI: 10.1182/blood.2023021545
PMID: 37944157


Nonmuscle 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 (MKs), which are the precursors to platelets, can be found in bone marrow and 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 MKs to compress plasma clots. Megakaryocytes derived from human induced pluripotent stem cells (iPSCs) 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 iPSC-derived MKs (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 2 kinetic phases with distinct rates and durations. It was suppressed by inhibitors of nonmuscle 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 MK 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. © 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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