Nature Communications ( IF 14.7 ) Pub Date : 2023-07-07 , DOI: 10.1038/s41467-023-39598-9
Xiaojuan Zhao 1 , Dominic Alibhai 2 , Tony G Walsh 1 , Nathalie Tarassova 1 , Maximilian Englert 3 , Semra Z Birol 1 , Yong Li 1 , Christopher M Williams 1 , Chris R Neal 2 , Philipp Burkard 3 , Stephen J Cross 2 , Elizabeth W Aitken 1 , Amie K Waller 4 , José Ballester Beltrán 4 , Peter W Gunning 5 , Edna C Hardeman 5 , Ejaife O Agbani 6 , Bernhard Nieswandt 3 , Ingeborg Hers 1 , Cedric Ghevaert 4 , Alastair W Poole 1
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Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms remain unclear. Outside the body, however, our ability to generate large number of functional platelets is poor. Here we show that perfusion of megakaryocytes ex vivo through the mouse lung vasculature generates substantial platelet numbers, up to 3000 per megakaryocyte. Despite their large size, megakaryocytes are able repeatedly to passage through the lung vasculature, leading to enucleation and subsequent platelet generation intravascularly. Using ex vivo lung and an in vitro microfluidic chamber we determine how oxygenation, ventilation, healthy pulmonary endothelium and the microvascular structure support thrombopoiesis. We also show a critical role for the actin regulator Tropomyosin 4 in the final steps of platelet formation in lung vasculature. This work reveals the mechanisms of thrombopoiesis in lung vasculature and informs approaches to large-scale generation of platelets.
中文翻译:
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通过微流体在肺血管系统中高效生成血小板
血小板是一种小的止血血细胞,源自巨核细胞。骨髓和肺都是血小板生成的主要部位,但潜在机制仍不清楚。然而,在体外,我们产生大量功能性血小板的能力很差。在这里,我们表明通过小鼠肺血管系统离体灌注巨核细胞会产生大量血小板,每个巨核细胞高达 3000 个。尽管巨核细胞体积很大,但它们能够反复穿过肺血管系统,导致去核并随后在血管内生成血小板。使用离体肺和体外微流体室,我们确定氧合、通气、健康肺内皮和微血管结构如何支持血小板生成。我们还展示了肌动蛋白调节剂原肌球蛋白 4 在肺血管系统血小板形成的最后步骤中的关键作用。这项工作揭示了肺血管系统中血小板生成的机制,并为大规模生成血小板的方法提供了信息。