Department of Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA 24061.
Department of Mechanical Engineering, Virginia Tech, Blacksburg, VA 24061.
Proc Natl Acad Sci U S A. 2021 Mar 23;118(12). doi: 10.1073/pnas.2011815118.
Contact inhibition of locomotion (CIL), in which cells repolarize and move away from contact, is now established as a fundamental driving force in development, repair, and disease biology. Much of what we know of CIL stems from studies on two-dimensional (2D) substrates that do not provide an essential biophysical cue-the curvature of extracellular matrix fibers. We discover rules controlling outcomes of cell-cell collisions on suspended nanofibers and show them to be profoundly different from the stereotyped CIL behavior on 2D substrates. Two approaching cells attached to a single fiber do not repolarize upon contact but rather usually migrate past one another. Fiber geometry modulates this behavior; when cells attach to two fibers, reducing their freedom to reorient, only one cell repolarizes on contact, leading to the cell pair migrating as a single unit. CIL outcomes also change when one cell has recently divided and moves with high speed-cells more frequently walk past each other. Our computational model of CIL in fiber geometries reproduces the core qualitative results of the experiments robustly to model parameters. Our model shows that the increased speed of postdivision cells may be sufficient to explain their increased walk-past rate. We also identify cell-cell adhesion as a key mediator of collision outcomes. Our results suggest that characterizing cell-cell interactions on flat substrates, channels, or micropatterns is not sufficient to predict interactions in a matrix-the geometry of the fiber can generate entirely new behaviors.
接触抑制运动（CIL）是指细胞重新极化并远离接触的过程，现已成为发育、修复和疾病生物学的基本驱动力。我们对 CIL 的了解主要来自于对二维（2D）底物的研究，这些底物不能提供一个基本的生物物理线索——细胞外基质纤维的曲率。我们发现了控制悬浮纳米纤维上细胞-细胞碰撞结果的规则，并表明它们与 2D 底物上的典型 CIL 行为有很大的不同。两个接近的细胞附着在单根纤维上，接触时不会重新极化，而是通常彼此迁移过去。纤维几何形状调节这种行为；当细胞附着在两根纤维上，减少它们重新定向的自由度时，只有一根细胞在接触时重新极化，导致细胞对作为一个整体迁移。当一个细胞最近分裂并高速移动时，CIL 的结果也会发生变化——细胞更频繁地彼此走过。我们的纤维几何形状 CIL 计算模型能够稳健地再现实验的核心定性结果，对模型参数的变化不敏感。我们的模型表明，分裂后细胞的速度增加可能足以解释它们增加的走过率。我们还确定细胞-细胞黏附是碰撞结果的关键介导因素。我们的结果表明，在平板、通道或微图案上对细胞-细胞相互作用进行特征描述不足以预测基质中的相互作用——纤维的几何形状可以产生全新的行为。
