Department of Mechanical Engineering, Virginia Tech, Blacksburg, VA, 24061, USA.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
Adv Sci (Weinh). 2022 Sep;9(25):e2203011. doi: 10.1002/advs.202203011. Epub 2022 Jul 21.
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.
细胞骨架介导的力传递调节核形态。然而,在类似于天然细胞外基质的纤维状环境中,细胞核是如何塑形的,目前仍知之甚少。在这里,使用精确可调(纳米-微米)直径的悬浮纳米纤维网络来量化纤维状环境中细胞核的可塑性。与细胞在二维表面上的细胞核上的顶端帽相反,纤维上的细胞的细胞骨架显示出均匀的肌动蛋白网络,将细胞核包围起来。研究了收缩力驱动的笼状作用在细胞在排列的单纤维、双纤维和不同直径的多纤维上扩展时对核形状的塑造作用。由于粘着斑聚类和肌动蛋白应力纤维的密度增加,细胞的收缩力随纤维直径的增加而增加,这与机械敏感转录因子 Yes 相关蛋白(YAP)向细胞核的易位增加相关。出乎意料的是,由于细胞中的应力纤维各向异性,大直径和小直径纤维的组合会导致泪珠形细胞核。当细胞在纤维上扩展时,在纤维接触点形成与纤维长度一致的直径依赖性核包膜内陷。富含异染色质聚类和 DNA 修复位点的最尖锐内陷不足以引发核破裂。总的来说,作者定量地研究了以前未知的细胞核对具有病理生理学意义的纤维状环境的塑造和适应性。