Tozluoglu Melda, Mao Yanlan, Bates Paul A, Sahai Erik
MRC/UCL Laboratory for Molecular Cell Biology, University College London, London, UK Biomolecular Modelling Laboratory, London Research Institute, Cancer Research UK, London, UK Tumour Cell Biology Laboratory, London Research Institute, Cancer Research UK, London, UK.
MRC/UCL Laboratory for Molecular Cell Biology, University College London, London, UK.
J R Soc Interface. 2015 May 6;12(106). doi: 10.1098/rsif.2014.1355.
Cells can move through extracellular environments with varying geometries and adhesive properties. Adaptation to these differences is achieved by switching between different modes of motility, including lamellipod-driven and blebbing motility. Further, cells can modulate their level of adhesion to the extracellular matrix (ECM) depending on both the level of force applied to the adhesions and cell intrinsic biochemical properties. We have constructed a computational model of cell motility to investigate how motile cells transition between extracellular environments with varying surface continuity, confinement and adhesion. Changes in migration strategy are an emergent property of cells as the ECM geometry and adhesion changes. The transition into confined environments with discontinuous ECM fibres is sufficient to induce shifts from lamellipod-based to blebbing motility, while changes in confinement alone within a continuous geometry are not. The geometry of the ECM facilitates plasticity, by inducing shifts where the cell has high marginal gain from a mode change, and conserving persistency where the cell can continue movement regardless of the motility mode. This regulation of cell motility is independent of global changes in cytoskeletal properties, but requires locally higher linkage between the actin network and the plasma membrane at the cell rear, and changes in internal cell pressure. In addition to matrix geometry, we consider how cells might transition between ECM of different adhesiveness. We find that this requires positive feedback between the forces cells apply on the adhesion points, and the strength of the cell-ECM adhesions on those sites. This positive feedback leads to the emergence of a small number of highly adhesive cores, similar to focal adhesions. While the range of ECM adhesion levels the cell can invade is expanded with this feedback mechanism; the velocities are lowered for conditions where the positive feedback is not vital. Thus, plasticity of cell motility sacrifices the benefits of specialization, for robustness.
细胞能够在具有不同几何形状和粘附特性的细胞外环境中移动。通过在不同的运动模式之间切换，包括片状伪足驱动的运动和气泡运动，细胞实现了对这些差异的适应。此外，细胞可以根据施加在粘附点上的力的水平以及细胞内在的生化特性来调节其与细胞外基质（ECM）的粘附水平。我们构建了一个细胞运动的计算模型，以研究运动细胞如何在具有不同表面连续性、限制和粘附性的细胞外环境之间转变。随着ECM几何形状和粘附性的变化，迁移策略的改变是细胞的一种涌现特性。过渡到具有不连续ECM纤维的受限环境足以诱导从基于片状伪足的运动转变为气泡运动，而在连续几何形状内仅限制的变化则不会。ECM的几何形状通过在细胞从模式变化中获得高边际收益的地方诱导转变，并在细胞无论运动模式如何都能继续移动的地方保持持续性，从而促进可塑性。这种细胞运动的调节与细胞骨架特性的全局变化无关，但需要在细胞后部的肌动蛋白网络和质膜之间局部更高的连接，以及细胞内压力的变化。除了基质几何形状，我们还考虑了细胞如何在不同粘附性的ECM之间转变。我们发现这需要细胞施加在粘附点上的力与这些位点上细胞 - ECM粘附的强度之间的正反馈。这种正反馈导致出现少量高度粘附的核心，类似于粘着斑。虽然通过这种反馈机制细胞能够侵入的ECM粘附水平范围扩大了；但在正反馈不关键的条件下速度会降低。因此，细胞运动的可塑性为了稳健性而牺牲了专业化的益处。
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