[论文解读] The role of vimentin-nuclear interactions in persistent cell motility through confined spaces

Sarthak Gupta, Alison E. Patteson+1 more|arXiv (Cornell University)|Mar 16, 2021

Cellular Mechanics and Interactions参考文献 81被引用 19

一句话总结

本研究提出了一种细胞在受限微通道中运动的最小计算模型，表明波形蛋白作为机械调节因子，将肌动蛋白-肌球蛋白皮层与细胞核连接起来。减少波形蛋白后，细胞核形变增加，细胞极性对受限环境的依赖性增强，从而提升运动的持续性——这解释了实验观察到的波形蛋白缺失细胞运动更快、更持久的现象。

ABSTRACT

The ability of cells to move through small spaces depends on the mechanical properties of the cellular cytoskeleton and on nuclear deformability. In mammalian cells, the cytoskeleton is comprised of three interacting, semi-flexible polymer networks: actin, microtubules, and intermediate filaments (IF). Recent experiments of mouse embryonic fibroblasts with and without vimentin have shown that the IF vimentin plays a role in confined cell motility. We, therefore, develop a minimal model of cells moving through confined geometries that effectively includes all three types of cytoskeletal filaments with a cell consisting of an actomyosin cortex and a deformable cell nucleus and mechanical connections between the two cortices the outer actomyosin one and the inner nuclear one. By decreasing the amount of vimentin, we find that the cell speed is typically faster for vimentin-null cells as compared to cells with vimentin. Vimentin-null cells also contain more deformed nuclei in confinement. Finally, vimentin affects nucleus positioning within the cell. By positing that as the nucleus position deviates further from the center of mass of the cell, microtubules become more oriented in a particular direction to enhance cell persistence or polarity, we show that vimentin-nulls are more persistent than vimentin-full cells. The enhanced persistence indicates that the vimentin-null cells are more subjugated by the confinement since their internal polarization mechanism that depends on cross-talk of the centrosome with the nucleus and other cytoskeletal connections is diminished. In other words, the vimentin-null cells rely more heavily on external cues. Our modeling results present a quantitative interpretation for recent experiments and have implications for understanding the role of vimentin in the epithelial-mesenchymal transition.

研究动机与目标

• 理解波形蛋白在三维空间中通过受限通道迁移时的机械作用。
• 解释实验观察到的波形蛋白缺失细胞运动速度和持续性增加的现象。
• 研究波形蛋白-细胞核连接在受限条件下对细胞核形变、定位和细胞极性的影响。
• 提出一种新机制，将细胞骨架强度、细胞核机械性能与受限环境中的方向持续性联系起来。

提出的方法

• 采用最小化的二维模型，模拟具有肌动蛋白-肌球蛋白皮层、可变形细胞核及其之间机械连接的细胞。
• 在细胞前缘和通道壁上施加肌动蛋白力以驱动运动，力通过弹簧模型表示。
• 波形蛋白以可调节的连接弹簧形式表示，连接肌动蛋白-肌球蛋白皮层与细胞核，其强度可调节以模拟波形蛋白的存在或缺失。
• 通过面积弹簧模型模拟细胞核形状与形变，抵抗压缩，同时追踪细胞核的圆形度与应变。
• 通过细胞核轴与通道轴之间夹角的分布来量化细胞运动的持续性。
• 通过改变参数（包括肌动蛋白力大小、连接弹簧强度、细胞核刚度和黏附力）来隔离波形蛋白的影响。

实验结果

研究问题

• RQ1 波形蛋白如何影响细胞在狭窄微通道中迁移时的速度与持续性？
• RQ2 波形蛋白在受限条件下对细胞核形变与定位起何作用？
• RQ3 波形蛋白缺失如何改变细胞骨架与细胞核之间的机械耦合？
• RQ4 能否通过机械模型解释实验观察到的波形蛋白缺失细胞运动持续性增加的现象？
• RQ5 在受限环境中，细胞核定位、细胞骨架力与细胞极性之间存在何种关系？

主要发现

• 在狭窄通道中，波形蛋白缺失细胞的运动速度高于野生型细胞，且随着通道宽度减小，速度进一步增加。
• 波形蛋白缺失导致细胞核形变更严重，细胞核定位发生改变，细胞核更倾向于与通道轴对齐。
• 波形蛋白缺失细胞表现出显著更高的运动持续性，表现为细胞核轴夹角分布图在90°（出口方向）附近出现更尖锐的峰值。
• 波形蛋白缺失细胞的细胞核应变增加，表明在穿越过程中细胞核承受更大的压缩应力。
• 该模型揭示了一种新极性机制：当波形蛋白缺失时，受限环境可增强方向持续性，使细胞对环境信号更敏感。
• 波形蛋白减少导致细胞核圆形度下降，表明在受限条件下细胞核形状畸变更严重，与实验观察到的核膜破裂现象一致。