A MULTISCALE MODEL OF CELL ADHESION AND MIGRATION ON EXTRACELLULAR MATRICES OF DEFINED STIFFNESS AND ADHESIVITY

摘要

Eukaryotic cells actively respond to variations in ligand density and stiffness of their extracellular matrix (ECM). This cell-ECM relationship plays an important role in regulating cell migration, wound healing, tumor invasion and metastasis. A better understanding of these mechanosenstive responses requires more rigorous models of the relationships between ECM biophysical properties, mechanotransductive signals, assembly of contractile and adhesive structures, and cell migration. We have developed a novel multiscale model of cell migration on ECMs of defined biophysical properties that integrates local activation of intracellular biochemical signals and force generation with adhesion dynamics at the cell-ECM interface and protrusion dynamics at the front of the cell. We capture the mechanosensitivity of individual cellular components by dynamically coupling ECM properties to the activation of Rho and Rac GTPases in specific regions of the cell with actin-myosin contractility, adhesive bond formation and rupture at the cell-ECM interface, and cell-level behaviors such as extension and retraction of migratory processes. Our model predicts for the first time recently reported transitions from filopodial to "stick-slip" to gliding motility on ECMs of increasing stiffness, previously observed biphasic dependences of migration speed on ECM stiffness and ligand density, and our own new high-resolution measurements of mechanosensitive protrusion dynamics during cell motility. The model also provides a mechanistic explanation of how the tendency of the cell to polarize might affect the biphasic dependence of cell migration speed on ECM stiffness. This model enables us to individually probe various parameters that affect cell-ECM interaction and simulate the cell migration response under extracellular conditions that may not be readily accessible in experiments.