Modeling cell migration regulated by cell extracellular-matrix micromechanical coupling

Abstract

Cell migration in fibreous extracellular matrix (ECM) is crucial to many physiological and pathological processes such as tissue regeneration, immune response and cancer progression. During migration, individual cells can generate active pulling forces via actin filament contraction, which are transmitted to the ECM fibers through focal adhesion complexes, remodel the ECM, and eventually propagate to and can be sensed by other cells in the system. The microstructure and physical properties of the ECM can also significantly influence cell migration, e.g., via durotaxis and contact guidance. Here, we develop a computational model for cell migration regulated by cell-ECM micro-mechanical coupling. Our model explicitly takes into account a variety of cellular level processes including focal adhesion formation and disassembly, active traction force generation and cell locomotion due to actin filament contraction, transmission and propagation of tensile forces in the ECM, as well as the resulting ECM remodeling. We validate our model by accurately reproducing single-cell dynamics of MCF-10A breast cancer cells migrating on collagen gels and show that the durotaxis and contact guidance effects naturally arise as a consequence of the cell-ECM micromechanical interactions considered in the model. Moreover, our model predicts strongly correlated multi-cellular migration dynamics, which are resulted from the ECM-mediated mechanical coupling among the migrating cell and are subsequently verified in in vitro experiments using MCF-10A cells. Our computational model provides a robust tool to investigate emergent collective dynamics of multi-cellular systems in complex in vivo micro-environment and can be utilized to design in vitro micro-environments to guide collective behaviors and self-organization of cells.

Simulating flow induced migration in vascular remodelling

“…ECs not only migrate in tandem; they also should interact with the avascular regions. These regions are often modelled as matrices with elastic or viscoelastic properties [ 27 , 28 ]; however, the avascular regions also consist of different types of cells that replicate and/or grow. Therefore, an agent-based model for the avascular regions is more appropriate.…”

Role of RhoC in cancer cell migration

“…In the process of migration, cells can produce an active pulling force through contraction of actin and myosin, to make cells move forward [ 143 ]. The contractile apparatus in cells consists of F-actin and myosin II.…”

Geometric Dependence of 3D Collective Cancer Invasion

“…To further test our hypothesis in explaining the observed contrast between circular and triangular tumors, we devise a multiscale computational model that takes into account the fibrous microstructure of the ECM (11,12) and nonlinear ECM mechanics (13)(14)(15), as well as cell motility directed by ECM mechanical cues (16)(17)(18)(19). In particular, in our simulations, the tumor diskoid is modeled as a 3D packing of (spherical) cells within a flat cylinder with a thickness of 100 mm (i.e., $4-5 cell lengths) (see Fig.…”