Physical biology of cell-substrate interactions under cyclic stretch

Abstract

Mechanosensitive focal adhesion complexes mediate the dynamic interactions between cells and substrates, and regulate cellular function. Integrins in adhesion complexes link substrate ligands to stress fibers in the cytoskeleton, and aid in load transfer and traction generation during cell adhesion and migration. A repertoire of signaling molecules, including calcium, facilitate this process. We develop a novel one-dimensional, multi-scale, stochastic finite element model of a fibroblast on a substrate which includes calcium signaling, stress fiber remodeling, and focal adhesion dynamics that describes the formation and clustering of integrins to substrate ligands. We link the stochastic dynamics involving motor-clutches at focal adhesions to continuum level stress fiber contractility at various locations along the cell length. The stochastic module links to a calcium signaling module, via IP3 generation, and adaptor protein dyanamics through feedback. We use the model to quantify changes in cellular responses with substrate stiffness, ligand density, and cyclic stretch. Results show that tractions and integrin recruitments vary along the cell length and depend critically on interactions between the stress fiber and reversibly engaging adaptor proteins. Maximum tractions and integrin recruitments were present at the lamellar regions. Cytosolic calcium increased with substrate stiffness and ligand density. The optimal substrate stiffness, based on maximum tractions exerted by the cell, shifted towards stiffer substrates at high ligand densities. Cyclic stretch increased the cytosolic calcium and tractions at lamellipodial and intermediate cell regions. Tractions and integrin recruitments showed biphasic responses with substrate stiffness that increased with ligand density under stretch. The optimal substrate stiffness under stretch shifted towards compliant substrates at a given ligand density. Cells deadhere under stretch, characterized by near-zero recruitments and tractions, beyond a critical substrate stiffness. The coupling of stress fiber contractility to adhesion dynamics is essential in determining cellular responses under external mechanical perturbations. Statement of SignificanceCells are exquisitely sensitive to substrate ligand density, stiffness, and cyclic stretch. How do cell-substrate interactions change under cyclic stretch? We use a systems biology approach to develop a one-dimensional, multi-scale, stochastic finite element model of cellular adhesions to substrates which includes focal adhesion attachment dynamics, stress fiber activation, and calcium signaling. We quantify tractions along the cell length in response to variations in substrate stiffness, cyclic stretching, and differential ligand densities. Calcium signaling changes the stress fiber contractility and focal adhesion dynamics under stretch and substrate stiffness. Cell tractions and adhesions show a biphasic response with substrate stiffness that increased with higher ligand density and cyclic stretch. Chemomechanical coupling is essential in quantifying mechanosensing responses underlying cell-substrate interactions.