Multinucleation resets human macrophages for specialized functions at the expense of their identity.
Multinucleation resets human macrophages for specialized functions at the expense of their identity.
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DOI：
10.15252/embr.202256310
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发表时间：
2023-03-06
期刊：
影响因子：
7.7
通讯作者：
中科院分区：
文献类型：
--
作者：
巨噬细胞经历质膜融合和细胞多核化，形成多核巨细胞（MGCs），如骨中的破骨细胞、作为肉芽肿一部分的郎汉斯巨细胞（LGC）或对外源性物质反应的异物巨细胞（FBGC）。多核化本身如何促进成熟单核巨噬细胞的功能特化在人类中仍然知之甚少。在这里，我们整合比较转录组学与纯化的成熟单核和多核人破骨细胞，LGC和FBGC的功能测定。引人注目的是，在所有三种类型的MGCs中，多核化导致巨噬细胞身份的显著下调。我们发现增强的溶酶体介导的细胞内铁稳态促进MGC形成。从单核到多核状态的转变伴随着对每个多核体特异性的细胞特化。增强的吞噬和线粒体功能分别与FBGC和破骨细胞相关。此外，人LGC优先表达B7-H3（CD 276），并可在体外形成肉芽肿样簇，表明其多核化增强T细胞活化。这些发现证明了细胞-细胞融合和多核化如何重置人类巨噬细胞身份，作为赋予MGC特异性功能的高级成熟步骤的一部分。巨噬细胞经历质膜融合和多核化以形成破骨细胞、郎汉斯巨细胞（LGC）或异物巨细胞（FBGC）。细胞融合以牺牲其身份为代价塑造了多核巨噬细胞的环境依赖性活动。
Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign‐body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome‐mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7‐H3 (CD276) and can form granuloma‐like clusters in vitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell–cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC‐specific functionality. Macrophages undergo plasma membrane fusion and multinucleation to form osteoclasts, Langhans giant cells (LGCs) or foreign‐body giant cells (FBGCs). Cell fusion shapes context‐dependent activities of multinucleated macrophages at the expense of their identity.
巨噬细胞螺旋细胞异源性。 I.制备和特性。
影响因子：
15.3
作者：
GORDON, S;COHN, Z
通讯作者：
COHN, Z
影响因子：
15.3
作者：
GORDON, S;COHN, Z
通讯作者：
COHN, Z