Adherent cells seeded on substrates spread and evolve their morphology while simultaneously displaying motility. Phenomena such as contact guidance viz. the alignment of cells on patterned substrates, are strongly linked to the coupling of morphological evolution with motility. Here we employ a recently developed statistical thermodynamics framework for modelling the non-thermal fluctuating response of the cells to probe this coupling. This thermodynamic framework is first extended to predict temporal responses via a Langevin style model. The Langevin model is then shown to not only predict the different experimentally observed temporal scales for morphological observables such as cell area and elongation but also the interplay of morphology with motility that ultimately leads to contact guidance.

Adherent cells seeded on substrates spread and evolve their morphology while simultaneously displaying motility. Phenomena such as contact guidance, viz. the alignment of cells on patterned substrates, are strongly linked to the coupling of morphological evolution with motility. Here, we employ a recently developed statistical thermodynamics framework for modelling the non-thermal fluctuating response of cells to probe this coupling. This thermodynamic framework is first extended via a Langevin style model to predict temporal responses of cells to unpatterned and patterned substrates. The Langevin model is then shown to not only predict the different experimentally observed temporal scales for morphological observables such as cell area and elongation but also the interplay of morphology with motility that ultimately leads to contact guidance.

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Cyclic strain avoidance, the phenomenon of cell and cytoskeleton alignment perpendicular to the direction of cyclic strain of the underlying two-dimensional substrate, is an important characteristic of the adherent cell organization. This alignment has typically been attributed to the stress-fiber reorganization although observations clearly show that stress-fiber reorganization under cyclic loading is closely coupled to cell morphology and reorientation of the cells. Here we develop a statistical mechanics framework that couples the cytoskeletal stress-fiber organisation with cell morphology under imposed cyclic straining and make quantitative comparisons with observations. The framework accurately predicts that cyclic strain avoidance stems primarily from cell reorientation away from the cyclic straining rather than cytoskeletal reorganisation within the cell. The reorientation of the cell is a consequence of the cell lowering its free-energy by largely avoiding the imposed cyclic straining. Furthermore, we investigate the kinetics of the cyclic strain avoidance mechanism and demonstrate that it emerges primarily due to the rigid body rotation of the cell rather than via a trajectory involving cell straining. Our results provide clear physical insights into the coupled dynamics of cell morphology and stress-fibers, which ultimately leads to cellular organization in cyclically strained tissues.