Mechanosensitive focal adhesion (FA) complexes mediate dynamic interactions between cells and substrates and regulate cellular function. Integrins in FA complexes link substrate ligands to stress fibers (SFs) and aid load transfer and traction generation. We developed a one-dimensional, multi-scale, stochastic finite element model of a fibroblast on a substrate that includes calcium signaling, SF remodeling, and FA dynamics. We linked stochastic dynamics, describing the formation and clustering of integrins to substrate ligands via motor-clutches, to a continuum level SF contractility model at various locations along the cell length. We quantified changes in cellular responses with substrate stiffness, ligand density, and cyclic stretch. Results show that tractions and integrin recruitments varied along the cell length; tractions were maximum at lamellar regions and reduced to zero at the cell center. Optimal substrate stiffness, based on maximum tractions exerted by the cell, shifted toward stiffer substrates at high ligand densities. Mean tractions varied biphasically with substrate stiffness and peaked at the optimal substrate stiffness. Cytosolic calcium increased monotonically with substrate stiffness and accumulated near lamellipodial regions. Cyclic stretch increased the cytosolic calcium, integrin concentrations, and tractions at lamellipodial and intermediate regions on compliant substrates. The optimal substrate stiffness under stretch shifted toward compliant substrates for a given ligand density. Stretch also caused cell deadhesions beyond a critical substrate stiffness. FA’s destabilized on stiff substrates under cyclic stretch. An increase in substrate stiffness and cyclic stretch resulted in higher fibroblast contractility. These results show that chemomechanical coupling is essential in mechanosensing responses underlying cell–substrate interactions.

机械敏感性粘着斑 (FA) 复合物介导细胞和基质之间的动态相互作用并调节细胞功能。 FA 复合物中的整合素将底物配体与应力纤维 (SF) 连接起来，并有助于负载转移和牵引力产生。我们开发了基质上成纤维细胞的一维、多尺度、随机有限元模型，其中包括钙信号传导、SF 重塑和 FA 动力学。我们将随机动力学（描述整合素通过马达离合器与底物配体的形成和聚集）与沿细胞长度不同位置的连续水平 SF 收缩性模型联系起来。我们通过基质硬度、配体密度和循环拉伸来量化细胞反应的变化。结果表明，牵引力和整合素招募沿着细胞长度变化。层状区域的牵引力最大，细胞中心的牵引力降至零。基于细胞施加的最大牵引力的最佳基底刚度转向高配体密度下更硬的基底。平均牵引力随基底刚度呈双相变化，并在最佳基底刚度处达到峰值。胞质钙随基质硬度单调增加并在板状足区域附近积累。循环拉伸增加了柔顺基质上片状足和中间区域的胞质钙、整合素浓度和牵引力。对于给定的配体密度，拉伸下的最佳基底刚度转向顺应基底。拉伸还会导致细胞粘连超过临界基材刚度。在循环拉伸下，FA 在硬质基材上不稳定。基质硬度和循环拉伸的增加导致成纤维细胞收缩性更高。这些结果表明，化学机械耦合对于细胞-基质相互作用的机械传感反应至关重要。