Three-dimensional computational modeling of pseduopod-driven amoeboid cells through extracellular matrix geometry

Migration of amoeboid cells is characterized by the formation of pseudopods, or extensions of the cell membrane which protrude outwards, bifurcate, and retract in a dynamic fashion. The study of the amoeboid morphology is immeasurably important, as many cells and processes within the body depend on pseudopod-based migration, such as the phagocytosing of foreign pathogens by immune cells, the extension of nerve axons during neural development, the repair of damaged connective tissue and skin by fibroblasts and epithelial cells, the migration of key progenitor cells during embryonic development, and the invasive propensity of cancer cells during metastasis. Amoeboid motility is a complex, multiscale process which involves extreme cell deformation, internalized and surface-bound biochemistry, and both cytoplasmic and extracellular fluid interactions. Additionally, cells are often immersed within a confining and complex heterogenous environment known as the Extracellular Matrix (ECM). The ECM and cell are fundamentally coupled to one another, where membrane deformability, surface protein diffusivity, fluid viscosity, matrix porosity, pore size, and alignment can alter the behavior and dynamics of a cell. In this dissertation, a three-dimensional computational model is presented in which pseudopod-driven amoeboid migration is analyzed in various geometries, and under varying cell parameters. Models are developed for the cell membrane, pseudopod pattern generator, extracellular matrix geometry, and fluid-cell/fluid-obstacle coupling, after which a detailed analysis is performed. The approach is based on use of immersed-boundary methods, which allow for seamless integration between the highly deformable cell, fluid, and arbitrarily-shaped extracellular geometry. Amoeboid swimming is first studied through an unbounded fluid domain, revealing effects caused through the alteration of membrane deformability, surface-protein diffusivity, and fluid viscosity. A regime change in cell dynamics, allowing the cell to transition from slow, random motion, to fast, persistent motion is observed in certain parameter ranges. Cell migration through various ECM geometries is then considered, where the influence of matrix porosity and obstacle size is added to the existing analysis. In addition to drastically altered behavior, interesting cell dynamics are seen due to cell-obstacle interactions. Finally, amoeboid locomotion is studied through an expanded assortment of ECM geometries, while a weak adhesion model characteristic of an amoeboid cell is adopted. In each case, a comprehensive study of cell behavior, pseudopod dynamics, and fluid field analysis is performed. The simulated cell is shown to be qualitatively similar in form to experiments, and quantitatively similar in regard to cell speed and dynamics. Insights into cell persistence, dynamics, and migration speed are given. Overall, this model pushes the forefront of the three-dimensional computational modeling of amoeboid cells, revealing fascinating behaviors, trends, and dynamics. Its continued refinement has the potential to reveal further mechanisms of amoeboid migration and the influence of tissue geometry on its behavior.Ph.D.Includes bibliographical reference