Integration of elasticity, viscosity, and plasticity in cellular mechanosensing

Project Summary/Abstract 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 investigations as part of the parent R01 project where 1) we demonstrated through theory and experiments that faster substrate stress relaxation leads to faster migration of healthy and diseased human cells, 2) we predicted through an active chemo-mechanical model in both 2D and 3D non-linear elastic microenvironments with increasing matrix stiffness, which correlates strongly with the change in mitochondrial potential, glucose uptake and ATP levels measured experimentally; and 3) we showed that physiological and pathological chemomechanical cues can directly regulate the spatial nanoscale organization. In this renewal our overall goal is to integrate theoretical and experimental studies to address how dissipative matrix properties regulate cellular metabolism, cytoskeletal activity, and chromatin organization, all vitally important determinants of cell fate and function. We propose an integrated approach using imaging, theoretical modeling, and omics data to elucidate the crosstalk between histone deacetylases (HDACs) and metabolism. We will emphasize understanding how the elastic and dissipative properties of the microenvironment, along with metabolites that act as histone deacetylase inhibitors (HDACIs), synergistically regulate HDAC activity and metabolic pathways.