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

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dc.contributor.authorKim, Oleg V.en
dc.contributor.authorLitvinov, Rustem I.en
dc.contributor.authorGagne, Alyssa L.en
dc.contributor.authorFrench, Deborah L.en
dc.contributor.authorBrass, Lawrence F.en
dc.contributor.authorWeisel, John W.en
dc.date.accessioned2023-11-10T13:15:47Zen
dc.date.available2023-11-10T13:15:47Zen
dc.date.issued2023en
dc.date.updated2023-11-10T01:57:27Zen
dc.description.abstractNon-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.en
dc.description.versionAccepted versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1182/blood.2023021545en
dc.identifier.eissn1528-0020en
dc.identifier.issn0006-4971en
dc.identifier.orcidKim, Oleg [0000-0003-1626-592X]en
dc.identifier.urihttp://hdl.handle.net/10919/116646en
dc.language.isoenen
dc.publisherAmerican Society of Hematologyen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject3101 Biochemistry and cell biologyen
dc.subject3201 Cardiovascular medicine and haematologyen
dc.subject3213 Paediatricsen
dc.titleMegakaryocyte-induced contraction of plasma clots: Cellular mechanisms and structural mechanobiologyen
dc.title.serialBlooden
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Engineeringen
pubs.organisational-group/Virginia Tech/Engineering/Biomedical Engineering and Mechanicsen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Engineering/COE T&R Facultyen

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