The Effects of Elasticity and Geometry on Cell Migration and Polarization

Abstract

Cell migration is a crucial process in the development and maintenance of the human body. Migration is also involved in a number of pathologies. In atherosclerosis, for example, immune cells migrate to the site of inflammation and contribute to the progression of the disease. In cancer, cells migrate out of the primary tumor through the body to metastasize at distant sites creating deadly secondary tumors. In all of these examples, cells confront and must adapt to a broad range of extracellular environments. Two important properties that cells encounter in the body are the elasticity of the environment and confinement. A better understanding of how a cell responds to these parameters would offer insights into the progression of diseases like cancer and atherosclerosis. Much cell migration research, however, has focused on cells moving on flat stiff substrates, like a glass culture dish. Therefore, in this dissertation, we investigated the effects of substrate elasticity and confinement on cell polarization and migration. First, macrophage behavior was studied on substrates of different stiffness. We found that macrophages are mechanosensitive and respond with changes in area, proliferation, and migration. To further investigate cell migration in response to stiffness we focused on polarization, the first step in directed cell migration, and found that the position of the centrosome, an organelle indicating polarity, was dependent on substrate elasticity. Micropatterned one-dimensional lines and a microfluidic device were used to study the effect of confinement on cell polarization and migration. We discovered that the centrosome position for cells migrating on lines is different than in two-dimensional migration and we also show the importance of microtubule polymerization forces in maintaining centrosome position. We used a microfluidic device to mimic the three-dimensional confinement cells encounter in the body. Under increased confinement, the centrosome position is more similar to migration on lines than on flat surfaces and is maintained even when cells change directions. These results demonstrate how the elasticity and confinement of a cell’s microenvironment affect cell polarization and migration. These results are important to further understand the role of these parameters in the progression of diseases like atherosclerosis and cancer.