Megakaryocyte-induced contraction of plasma clots: Cellular mechanisms and structural mechanobiology.
Megakaryocyte-induced contraction of plasma clots: Cellular mechanisms and structural mechanobiology.
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DOI：
10.1182/blood.2023021545
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发表时间：
2023-11
期刊：
影响因子：
20.3
通讯作者：
Oleg V Kim;R. Litvinov;Alyssa L. Gagne;Deborah L French;Lawrence F. Brass;J. Weisel
中科院分区：
文献类型：
--
作者：
Oleg V Kim;R. Litvinov;Alyssa L. Gagne;Deborah L French;Lawrence F. Brass;J. Weisel
非肌细胞收缩性是多种细胞过程的基本特征，如运动性、形态发生、分裂和基因组复制、细胞内转运和分泌。血凝块收缩是由收缩的血小板驱动的充分研究的过程。巨核细胞是血小板的前体，可以在骨髓和肺中找到。虽然它们表达许多与血小板中发现的相同的蛋白质和结构，但对其与细胞外蛋白（如纤维蛋白和收缩）结合的能力知之甚少。在这里，我们测量了巨核细胞压缩血浆凝块的能力。将来源于人诱导多能干细胞（iMK）的巨核细胞悬浮于人无血小板血浆中，并用凝血酶刺激。使用实时宏观光学跟踪、共聚焦显微镜和生物力学测量，我们发现激活的iMK引起宏观体积凝块收缩，以及通过纤维蛋白附着的质膜突起进行导致纤维蛋白纤维缩短和弯曲的伸展-收缩循环而使纤维蛋白网络致密化和硬化。由iMK诱导的收缩涉及具有不同速率和持续时间的两个动力学阶段。它被非肌肉肌球蛋白IIA、肌动蛋白聚合和整合素αIIbβ3-纤维蛋白相互作用的抑制剂抑制，表明iMK收缩性的分子机制与活化血小板中的相似或相同。我们的发现为巨核细胞生物力学提供了新的见解，并表明iMK可用作研究血小板收缩性的模型系统。在生理学上，MK收缩血浆凝块的能力可能在血管内血凝块和血栓的机械重塑中起作用。
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.