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Mechanically-Driven Pattern Formation in Cell Cultures

Authors: João R. D. Ramos

Supervisors: João Carvalho, Rui Travasso

MSc thesis, Universidade de Coimbra (2016)

Abstract: Cell migration is a fundamental mechanism which enables several biological phenomena, for example, embryogenesis, vasculogenesis, angiogenesis and immune system response, to occur and it is still not fully understood. Complications and diseases often arise from faults during this process. Effectively, cell migration is a hallmark of malignant cancer cells. By studying emergent patterns of cells, it is possible to shed light on this mechanism. Here, a hybrid two-dimensional (2D) model of cell dynamics couples a finite element method (FEM), for extracellular matrix (ECM) deformations, with a cellular Potts model (CPM), for cell movement and adhesion. A model for traction force generation and another for sensing mechanical environmental cues were used to couple the FEM to the CPM. This model was used to study mechanically-driven emergent cell behavior. Image analysis methods were adapted in order to classify and quantify the morphology of resulting patterns. In the context of vasculogenesis, results show that for certain values of cell-cell adhesion and cell traction force there is a maximum on the average number of meshes and that, by lowering cell-cell adhesion cost, the average mesh size increases, while the average number of meshes decreases. Furthermore, mechanical cues coupled with cell-cell adhesion were found to be able to pull multiple cells from a soft substrate into a stiffer substrate. Sprouting angiogenesis was also tested and, even though proliferation is not contemplated in the model, mechanical cues are enough to polarize cells on the surface of a spheroid and start forming sprouts. Cells with larger traction forces lead to longer sprouts, more bifurcations and observation of anastomosis, suggesting that tip cells have a stronger grip on the ECM. Finally, an avascular tumor was simulated. Mechanical feedback accounts for an uneven surface of the tumor. Metastatic cell invasion capabilities increase with traction force and mechanical cues resulting from those cells cause protrusions of normal tumor cells at the surface.