The interplay between cell-cell and cell-substrate interactions is complex yet necessary for the formation and healthy functioning of tissues. The same mechanosensing mechanisms used by the cell to sense its extracellular matrix also play a role in intercellular interactions. We used the discrete element method to develop a computational model of a deformable cell that includes subcellular components responsible for mechanosensing. We modeled a three-dimensional cell pair on a patterned (two-dimensional) substrate, a simple laboratory setup to study intercellular interactions. We explicitly modeled focal adhesions and adherens junctions. These mechanosensing adhesions matured, becoming stabilized by force. We also modeled contractile stress fibers that bind the discrete adhesions. The mechanosensing fibers strengthened upon stalling. Traction exerted on the substrate was used to generate traction maps (along the cell-substrate interface). These simulated maps are compared to experimental maps obtained via traction force microscopy. The model recreates the dependence on substrate stiffness of the tractions' spatial distribution, contractile moment of the cell pair, intercellular force, and number of focal adhesions. It also recreates the phenomenon of cell decoupling, in which cells exert forces separately when substrate stiffness increases. More importantly, the model provides viable molecular explanations for decoupling: mechanosensing mechanisms are responsible for competition between different fiber-adhesion configurations present in the cell pair. The point at which an increasing substrate stiffness becomes as high as that of the cell-cell interface is the tipping point at which configurations that favor cell-substrate adhesion dominate over those favoring cell-cell adhesion. This competition is responsible for decoupling.

中文翻译：

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细胞间粘附刚度调节细胞解耦作为底物刚度的函数

细胞 - 细胞和细胞 - 底物相互作用之间的相互作用是复杂的，但对于组织的形成和健康运作是必要的。细胞用来感知其细胞外基质的相同机械传感机制也在细胞间相互作用中发挥作用。我们使用离散元方法开发了可变形细胞的计算模型，其中包括负责机械传感的亚细胞成分。我们在图案化（二维）基板上模拟了一个三维细胞对，这是一个用于研究细胞间相互作用的简单实验室设置。我们明确地模拟了粘着斑和粘附连接。这些机械传感粘连成熟，通过力量变得稳定。我们还模拟了结合离散粘连的收缩应力纤维。机械传感纤维在失速时增强。施加在基板上的牵引力用于生成牵引力图（沿细胞-基板界面）。这些模拟图与通过牵引力显微镜获得的实验图进行比较。该模型重建了牵引空间分布、细胞对的收缩力矩、细胞间力和粘着斑数量对基质刚度的依赖性。它还重现了细胞解耦现象，其中当基板刚度增加时，细胞分别施加力。更重要的是，该模型为解耦提供了可行的分子解释：机械传感机制负责细胞对中存在的不同纤维粘附配置之间的竞争。增加的基板刚度变得与细胞 - 细胞界面一样高的点是有利于细胞 - 基板粘附的配置优于有利于细胞 - 细胞粘附的配置的临界点。本次比赛负责脱钩。