Lung megakaryocytes (Mks) are largely extravascular with an immune phenotype (1). Because bone marrow (BM) Mks are short lived, it has been assumed that extravascular lung Mks are constantly “seeded” from the BM. To investigate lung Mk origins and how origin affects their functions, we developed methods to specifically label lung Mks using CFSE dye and biotin delivered via the oropharyngeal route. Labeled lung Mks were present for up to 4 months, while BM Mks had a lifespan of less than 1 week. In a parabiosis model, lung Mks were partially replaced over 1 month from a circulating source. Unlike tissue-resident macrophages, using MDS1^-Cre-ERT2 TdTomato mice, we found that lung Mks arose from hematopoietic stem cells. However, studies with FlkSwitch mTmG mice showed that lung Mks were derived from a Flt3-independent lineage that did not go through a multipotent progenitor. CFSE labeling to track lung Mk–derived platelets showed that approximately 10% of circulating platelets were derived from lung-resident Mks at steady state, but in sterile thrombocytopenia this was doubled (~20%). Lung-derived platelets were similarly increased in a malaria infection model (Plasmodium yoelii) typified by thrombocytopenia. These studies indicate that lung Mks arise from a Flt3^– BM source, are long-lived, and contribute more platelets during thrombocytopenia.

中文翻译：

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长寿命肺巨核细胞有助于血小板减少症模型中的血小板恢复


肺巨核细胞 （Mks） 主要位于血管外，具有免疫表型 （1）。由于骨髓 （BM） Mks 的寿命很短，因此人们认为血管外肺 Mks 不断从 BM 中“播种”。为了研究肺 Mk 起源以及起源如何影响其功能，我们开发了使用 CFSE 染料和通过口咽途径递送的生物素特异性标记肺 Mks 的方法。标记的肺 Mks 存在长达 4 个月，而 BM Mks 的寿命不到 1 周。在共生模型中，肺 Mks 在 1 个月内从循环来源部分替代。与组织驻留巨噬细胞不同，使用 ^{MDS1-Cre-ERT2} TdTomato 小鼠，我们发现肺 Mks 起源于造血干细胞。然而，对 FlkSwitch mTmG 小鼠的研究表明，肺 Mks 来源于 Flt3 非依赖性谱系，该谱系没有经过多能祖细胞。用于跟踪肺 Mk 衍生血小板的 CFSE 标记显示，大约 10% 的循环血小板来自稳态下的肺驻留 Mks，但在无菌性血小板减少症中，这一比例增加了一倍 （~20%）。在以血小板减少症为代表的疟疾感染模型 （Plasmodium yoelii） 中，肺源性血小板同样增加。这些研究表明，肺 Mks 来自 ^Flt3-BM 来源，寿命长，并且在血小板减少症期间贡献更多的血小板。