The Response of Cells to the Mechanical Environment: A Numerical Investigation of the Actin Cytoskeleton and Cell Adhesion
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Numerous in-vitro studies have established that cells possess the ability to sense and react to their physical environment. However, the mechanisms underlying such mechanotransduction are poorly understood. Previous cell models neglect the active biomechanical cell processes that allow the cell to interact with the physical environment; therefore, ad-hoc adjustment of passive material properties is required. The main objective of this thesis is to develop and implement a computational framework that incorporates stress fibre (SF) contractility and remodelling and focal adhesion (FA) formation and evolution in a fully 3D environment to better understand the biophysical processes underlying the mechanical behaviour of cells. SF formation in this fully predictive implementation is allowed to occur in any direction at every point in the cell cytoplasm. A thermodynamic FA formulation is expanded to consider both specific and non-specific adhesion dynamics under mixed mode conditions. The FA implementation is also entirely predictive; FA formation is driven by SF contractility and remodelling. Compression of single cells is simulated for round and spread cells, and for fully 3D elongated and irregularly shaped cells. The effect of cell shape and contractility on the compression response of cells is examined, revealing that tension in dominant SF bundles acts to restrict the deformation of the cell, increasing the resistance to compression. The 3D framework successfully parses the contributions of SF contractility, the nucleus, and the cytoplasm to the mechanical behaviour of osteoblasts. The mixed mode FA interaction model is used with the 3D SF framework to examine the effect of substrate stiffness on SF and FA formation. Results reveal that SF contractility plays a critical role in the substrate-dependent response of cells. Compliant substrates do not provide sufficient tension for stress fibre persistence, causing dissociation of stress fibres and lower focal adhesion formation. The simulations elucidate the link between substrate stiffness, SF formation, and nucleus stress, providing insight into the relationship between substrate stiffness and regulation of stem cell differentiation observed experimentally. The predictions of this mutually dependent material-interface framework are strongly supported by experimental observations of cells adhered to elastic substrates and of cells subjected to whole cell compression.
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