Physical principles of cell migration in confining and structured environments

Single cells migrating in physiological contexts face a common physical challenge: Both in two- and three-dimensional systems, such as epithelial sheets or connective tissue, cells migrate through complex confining environments. However, the physical principles underlying the migration dynamics of cells in such structured environments remain elusive.

We aim to develop a theoretical understanding of how physical interactions between migrating cells and their environment affect and control their dynamics. To this end, we employ a high-throughput approach using arrays of micropatterns to study migrating cells in 2D and 3D confining environments (Rädler B01). In the previous funding period, we found that cells confined to 2D micropatterns exhibit intricate non-linear migratory dynamics. Using a data-driven theoretical approach, we next aim to uncover the emergent shape dynamics and cell-cell interactions in confinement. We strive to elucidate how this system-level nonlinear behavior emerges from the internal dynamics. Specifically, we employ a simple model describing the cell as an active polarizable particle, with an effective interaction between the polarization dynamics and the geometry of the environment. This approach will be complemented using a more detailed Cellular Potts Model (with Frey B02). Confining environments also impact collective cell migration. With Zahler (B08), we will investigate the collective escape dynamics of cohesive groups of cells from 2D confining geometries. To study how cells migrate in more physiological environments, we develop a mechanical model of cells on a fibrous extracellular matrix, capturing cell-matrix interactions down to the scale of individual fibers. Our goal is to clarify how cell behavior is controlled by the interplay between cell-generated stresses and physical matrix features, including structural heterogeneity, elastic nonlinearity, and plasticity (Bausch A10, Zahler B08, Thorn-Seshold B09, Engelke B11). We aim to apply this model to help understand the mechanics and dynamics of epithelia in 2D and 3D complex confining geometries, such as angiogenesis (Zahler B08) or organoid development (Bausch A10).
Our work thus aims to provide new quantitative methods with which the stochastic dynamics of cells can be measured, analyzed and interpreted, leading to a potentially new physical characterization of cell migration in complex environments.