Physical Determinants of Cell Mechanics and Behavior
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CitationWu, Huayin. 2019. Physical Determinants of Cell Mechanics and Behavior. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe mechanical properties of cells govern many aspects of their behavior. Furthermore, cells can actively modify their mechanics in response to their environment. These properties are complex in origin, ranging from contributions by the internal cytoskeleton to intercellular interactions, and they reveal important clues about normal cell function as well as the underlying mechanisms in many diseases. In this thesis, we seek to better understand some of the physical influences on cell behavior using imaging-based techniques to probe the structure and mechanics of cells and their cytoskeletal proteins. While microtubules and actin have been studied in great detail, intermediate filaments have received much less attention, and much is still unknown about their fundamental properties. We thus begin by characterizing the viscoelastic properties of reconstituted vimentin intermediate filaments (VIFs) that have been crosslinked by two biologically-important divalent cations, Zn2+ and Ca2+. We find that these cations are able to significantly affect the rheological properties of vimentin but within vastly different concentrations ranges. We also observe binding competition between species. These results suggest that vimentin is well-suited to help cells respond to external stresses, which often bring changes in intracellular ion concentrations. We next investigate interactions between vimentin and actin within live cells. Although actin is responsible for force generation, vimentin is specifically expressed in very motile cells during development, wound healing, and cancer metastasis; here, we indeed find that vimentin has specific interactions with the actin cytoskeleton that can influence cell contractility and potentially many other processes. Lastly, we take a step back from the study of intracellular mechanics to consider the effects of applying a long-term stress to cells. In particular, chronic osmotic pressure is common in lung diseases, yet many studies have focused on biological mechanisms of disease rather than physical ones. However, osmotically compressing cells causes the expulsion of water, which concentrates the proteins, ions, and other macromolecules. We find that long-term osmotic pressure has important impacts on cell migration behavior and biology in ways that are characteristic of cystic fibrosis.
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