The role of mechanics in determining cell phenotype has been intensely studied since pioneering studies showed that cells in culture respond to differences in the elastic modulus of their environment. Stiffness sensing has been demonstrated in such varied settings as development, cancer, wound healing and fibrosis. How cells sense stiffness remains unclear, partly because of a lack of quantitative data that define exactly what cells sense, especially in vivo. In particular, the nature of viscoelasticity and non-linear (strain-dependent) elasticity and mechanical plasticity in normal and diseased tissues is insufficiently characterized, and the contribution of these mechanical parameters to cell stiffness sensing and behavior is not understood. This proposal extends studies of elasticity to encompass additional biologically relevant parameters, with a focus on the role of dissipative processes, and offers the potential to reevaluate current models of mechanobiology and develop new concepts of the role of time dependent mechanics in biological contexts. The proposed work builds on a series of our recent investigations where we have developed theoretical models to describe the non-linear and dissipative behavior of fibrous ECMs and stochastic models to analyze the dynamics of clutches (i.e., focal adhesions) formed between the cell and a substrate. We propose to investigate the impact of ECM viscosity, plasticity and non-linear elasticity on cell spreading and focal adhesion growth; specifically, to develop a detailed understanding of the relationship between the competition between intrinsic cellular timescales and characteristic timescales that determine the dissipative processes in the ECM, based on the hypothesis that viscous and plastic dissipation can be as important as the well-studied case of elastic moduli in determining cell response. We propose to a) Assess the role of viscous and elastic constituents of a matrix on cellular mechanosensing, b) Model and measure the effect of fiber realignment in collagen matrices on mechanosensing, adhesion dynamics, and cellular behavior and c) Define the reciprocal relation between viscoplastic remodeling of collagen networks and cellular mechanosensing.
An integrated approach utilizing computational modeling, in vitro and in vivo experimentation will be used to study the role of non-linear elasticity, viscosity and plasticity on focal adhesion dynamics and mechanosensing in cells. These theoretical models and experiments will enable us to better understand the impact of changes in tissue viscoelasticity and plasticity that are increasingly documented to contribute to progression of diseases such as cancer and fibrosis.
