Shu Wenya, Kaplan C Nadir
Department of Physics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; Center for Soft Matter and Biological Physics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
Department of Physics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; Center for Soft Matter and Biological Physics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia; Center for the Mathematics of Biosystems, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
Biophys J. 2025 Jun 24. doi: 10.1016/j.bpj.2025.06.020.
Mesenchymal cells navigate the extracellular matrix (ECM) in vivo by processing both its mechanical properties and confinement geometry. Here, we develop a multiscale whole-cell theory to investigate cell spreading and migration in two-dimensional viscoelastic channel confinements of varying width and curvature. Our simulations show that, in straight channels, the cell migration speed depends monotonically on the substrate elastic stiffness, which is otherwise biphasic on an unconfined substrate. This is because confinement enforces directional spreading while reducing the spreading area, which results in lower intracellular viscous drag on the nucleus and a higher net traction force of polarized cells in our model. In contrast, we find that confinement curvature slows down cell migration since the friction forces between the bending cell and the confinement walls increase with curvature. We validate our model with experimental data for cell migration in straight channels spanning a wide range of the ECM stiffness as well as in curved channels. Our model illuminates the intertwined effects of substrate viscoelasticity and confinement geometry on cell spreading and migration in complex microenvironments, revealing that channel curvature can override substrate mechanics to dominate migration regulation. The study paves the way for designing scaffolds that leverage curvature and confinement to steer controllable cell migration.
间充质细胞在体内通过处理细胞外基质（ECM）的力学特性和限制几何形状来在其中导航。在此，我们开发了一种多尺度全细胞理论，以研究细胞在具有不同宽度和曲率的二维粘弹性通道限制中的铺展和迁移。我们的模拟表明，在直通道中，细胞迁移速度单调依赖于底物弹性刚度，而在无限制的底物上则呈双相变化。这是因为限制会强制细胞定向铺展，同时减小铺展面积，这导致在我们的模型中细胞核上的细胞内粘性阻力降低，以及极化细胞的净牵引力更高。相比之下，我们发现限制曲率会减缓细胞迁移，因为弯曲的细胞与限制壁之间的摩擦力会随着曲率增加。我们用跨越广泛ECM刚度范围的直通道以及弯曲通道中细胞迁移的实验数据验证了我们的模型。我们的模型阐明了底物粘弹性和限制几何形状对复杂微环境中细胞铺展和迁移的交织影响，揭示了通道曲率可以超越底物力学来主导迁移调控。该研究为设计利用曲率和限制来引导可控细胞迁移的支架铺平了道路。
