Bagchi Amrit, Sarker Bapi, Zhang Jialiang, Foston Marcus, Pathak Amit
Department of Mechanical Engineering & Materials Science, Washington University, St. Louis, Missouri, United States of America.
Department of Energy, Environmental & Chemical Engineering, Washington University, St. Louis, Missouri, United States of America.
PLoS Comput Biol. 2025 Jan 9;21(1):e1012664. doi: 10.1371/journal.pcbi.1012664. eCollection 2025 Jan.
Cell collectives, like other motile entities, generate and use forces to move forward. Here, we ask whether environmental configurations alter this proportional force-speed relationship, since aligned extracellular matrix fibers are known to cause directed migration. We show that aligned fibers serve as active conduits for spatial propagation of cellular mechanotransduction through matrix exoskeleton, leading to efficient directed collective cell migration. Epithelial (MCF10A) cell clusters adhered to soft substrates with aligned collagen fibers (AF) migrate faster with much lesser traction forces, compared to random fibers (RF). Fiber alignment causes higher motility waves and transmission of normal stresses deeper into cell monolayer while minimizing shear stresses and increased cell-division based fluidization. By contrast, fiber randomization induces cellular jamming due to breakage in motility waves, disrupted transmission of normal stresses, and heightened shear driven flow. Using a novel motor-clutch model, we explain that such 'force-effective' fast migration phenotype occurs due to rapid stabilization of contractile forces at the migrating front, enabled by higher frictional forces arising from simultaneous compressive loading of parallel fiber-substrate connections. We also model 'haptotaxis' to show that increasing ligand connectivity (but not continuity) increases migration efficiency. According to our model, increased rate of front stabilization via higher resistance to substrate deformation is sufficient to capture 'durotaxis'. Thus, our findings reveal a new paradigm wherein the rate of leading-edge stabilization determines the efficiency of supracellular collective cell migration.
细胞集体，如同其他可移动的实体一样，会产生并利用力来向前移动。在此，我们探讨环境配置是否会改变这种力与速度的比例关系，因为已知排列整齐的细胞外基质纤维会引发定向迁移。我们发现，排列整齐的纤维充当了细胞机械转导通过基质外骨骼进行空间传播的主动通道，从而实现高效的定向集体细胞迁移。与随机纤维（RF）相比，贴附在带有排列整齐的胶原纤维（AF）的柔软基质上的上皮（MCF10A）细胞簇迁移速度更快，且牵引力更小。纤维排列会引发更高的运动波，并将法向应力更深地传递到细胞单层中，同时使剪切应力最小化，并增加基于细胞分裂的流化作用。相比之下，纤维随机化会由于运动波的中断、法向应力传递的破坏以及剪切驱动流的增强而导致细胞阻塞。通过使用一种新颖的马达 - 离合器模型，我们解释了这种“力有效”的快速迁移表型是由于迁移前沿收缩力的快速稳定所致，这是由平行纤维 - 基质连接的同时压缩加载产生的更高摩擦力所促成的。我们还对“趋触性”进行了建模，以表明增加配体连接性（而非连续性）会提高迁移效率。根据我们的模型，通过对底物变形的更高抗性来提高前沿稳定速率足以捕捉“硬度趋化性”。因此，我们的研究结果揭示了一种新的范式，即前沿稳定速率决定了超细胞集体细胞迁移的效率。
