Dynamic Cell Model with Cellular Signaling Network and Mechanical Forces for Tissue Pattern Formation
thesisposted on 17.02.2017 by Jieling Zhao
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Cells are the basic functional elements of living bodies. Cell-cell and cell-environment interactions largely maintain and regulate the processes of tissue formation and tissue regeneration, which involve collective cell migration and proliferation at large scale. Understanding the mechanisms behind cellular physiological processes such as embryo development, wound healing, and tumor metastasis requires study of cell-cell and cell-environment interactions, and their effects on cellular behaviors. As many underlying subcellular processes such as the generation of physical forces by cytoskeleton and transmitted mechanical forces through intercellular adhesion are difficult to access through direct experiments, computational cell model is useful for gaining insight into the mechanisms of cellular processes and aid in design of further investigations. A number of computational cell models have been developed to study cellular processes. However, all have limitations. They either lack accurate descriptions of cell shapes or cell mechanics, or have limited flexibility in modeling cell movements. These limitations prevent effective modeling of dynamic changes in cell shapes and mechanics in biological processes involving large scale cell migration. Here I develop a novel computational cell model called dyCelFEM. It accounts for detailed changes in cellular shapes and mechanics of individual cells in a large population of interacting cells. In addition, it can model the full range of cell motions, from free movement of individual cells to large scale collective cell migration. Furthermore, the transmission of mechanical forces via intercellular adhesion and its rupture is also modeled. With the intercellular protein signaling networks embedded in individual cells, biochemical control of cell behaviors can also be modeled. The dyCelFEM model is then employed to study two cellular processes, namely, the wound healing and cell movement on ECM. Wound healing is a complex process to repair the injured tissue through the communication and collaboration of multiple different types of cells and multiple growth factors and cytokines. Due to its complexity, the underlying cellular mechanisms, such as how the large scale collective cell motions during wound healing are regulated by different type of signals, are still not fully understood. Here I studied the effects of both biochemical and mechanical cues in regulating human skin wound healing and explored their roles in determining the tissue patterns. The cell movement under the effect of cell-ECM interaction is a process of environment sensing of living cell through cellular interaction. In the past decade, it has been found that cell behaves in response to a variety of physical cues from environment through the cell-ECM adhesions. Here I studied the specific role of the ECM geometry on regulating cell elongation and directing cell migration. The overall findings from this study establishes quantitative biological relevance of biochemical and mechanical effects on wound healing and effect of cell-ECM interaction on cell movement. It leads to a better understanding of the mechanisms behind complex processes of wound healing and cell movement on ECM.