Sculpting Rupture-Free Nuclear Shapes in Fibrous Environments.
Sculpting Rupture-Free Nuclear Shapes in Fibrous Environments.
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DOI：
10.1002/advs.202203011
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发表时间：
2022-09
期刊：
影响因子：
15.1
通讯作者：
Nain, Amrinder S.
中科院分区：
文献类型：
--
作者：
Jana, Aniket;Tran, Avery;Gill, Amritpal;Kiepas, Alexander;Kapania, Rakesh K.;Konstantopoulos, Konstantinos;Nain, Amrinder S.
关键词：
细胞骨架介导的力传递调节细胞核形态。细胞核如何在体内纤维环境中成形仍知之甚少。在这里，使用精确可调（nm-µm）直径的悬浮微球网络来量化模拟天然细胞外基质的纤维环境中的细胞核可塑性。与二维表面上细胞核上的顶帽相反，纤维上细胞的细胞骨架显示出包裹细胞核的均匀肌动蛋白网络。当细胞在排列的单纤维、双纤维和不同直径的多纤维上扩散时，研究了收缩驱动的笼状化在塑造细胞核形状中的作用。细胞收缩性随着纤维直径的增加而增加，这是由于增加的粘着斑聚集和肌动蛋白应力纤维的密度，这与增加的机械敏感性转录因子Yes相关蛋白（雅普）易位到细胞核相关。出乎意料的是，大直径和小直径纤维的组合由于细胞中的应力纤维各向异性而导致泪滴形核。当细胞在纤维上扩散时，在纤维接触部位形成直径依赖性的核被膜内陷，其贯穿细胞核的长度。富含异染色质簇和DNA修复位点的最尖锐的内陷不足以触发细胞核破裂。总体而言，作者量化了以前未知的雕刻和适应性的核纤维环境与病理生理学的影响。ECM模拟纤维环境中改变的顶基底极性通过纤维曲率驱动的收缩性塑造无破裂核。单纤维上的细胞在纤维特异性位点具有深的核内陷，导致异染色质的优先富集和DNA损伤。力驱动的多纤维细胞核压缩与增强的雅普核转位相关。由于肌动蛋白应力纤维分布的各向异性，直径不匹配的组合导致泪滴形核。
Cytoskeleton‐mediated force transmission regulates nucleus morphology. How nuclei shaping occurs in fibrous in vivo environments remains poorly understood. Here suspended nanofiber networks of precisely tunable (nm–µm) diameters are used to quantify nucleus plasticity in fibrous environments mimicking the natural extracellular matrix. Contrary to the apical cap over the nucleus in cells on 2‐dimensional surfaces, the cytoskeleton of cells on fibers displays a uniform actin network caging the nucleus. The role of contractility‐driven caging in sculpting nuclear shapes is investigated as cells spread on aligned single fibers, doublets, and multiple fibers of varying diameters. Cell contractility increases with fiber diameter due to increased focal adhesion clustering and density of actin stress fibers, which correlates with increased mechanosensitive transcription factor Yes‐associated protein (YAP) translocation to the nucleus. Unexpectedly, large‐ and small‐diameter fiber combinations lead to teardrop‐shaped nuclei due to stress fiber anisotropy across the cell. As cells spread on fibers, diameter‐dependent nuclear envelope invaginations that run the nucleus's length are formed at fiber contact sites. The sharpest invaginations enriched with heterochromatin clustering and sites of DNA repair are insufficient to trigger nucleus rupture. Overall, the authors quantitate the previously unknown sculpting and adaptability of nuclei to fibrous environments with pathophysiological implications. Altered apicobasal polarity in ECM‐mimicking fibrous environments sculpts rupture‐free nuclei through fiber curvature‐driven contractility. Cells on single fibers have deep nucleus invaginations at fiber‐specific sites causing preferential enrichment of heterochromatin and DNA damage. Force‐driven nuclear compression in cells on multiple fibers correlates with enhanced YAP nuclear translocation. Mismatch‐diameter combinations lead to teardrop‐shaped nuclei due to anisotropy in actin stress‐fiber distribution.
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