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Title: Investigations of geometric cues on cell physiology in vitro
Author: von Erlach, Thomas
ISNI:       0000 0004 5349 0963
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Cells in the human body show drastic differences in shape and morphology depending on the tissue that they are embedded in, and pathological tissue is often accompanied by changes in cell architecture. However, the question of whether changes in cell architecture play a regulatory role in physiology and disease is still mostly unexplored. As the cell architecture is influenced by the cell micro environment, such as the surrounding ECM, it might play a central role as a regulator and mediator of physical, or even chemical, environmental cues in vivo. As it is not possible to study the effect of cell architecture in vivo, various in vitro bioengineering systems based on microfabrication were developed in this thesis. The use of cell micropatterns allowed precise engineering of cell geometry, which was found to result in specific cell cytoskeletal arrangements and changes in cell contractility. It was found that those changes in contractility mediate cell geometry-dependent lineage commitment of mesenchymal stem cells. Development of several new analytical techniques and subsequent application to cell micropattern systems resulted in many new and unexpected cell geometry-dependent effects. For the first time, a link between lipid raft formation and cellcell geometry was observed. Additionally, plasma membrane curvature as a new cell characteristic is described and reported to be cell geometry-dependent in this thesis. Furthermore, a new mechanism involving lipid raft dependent Akt signalling was found to mediate cell geometry-dependent stem cell lineage commitment independent of PI3K activity in mesenchymal stem cells. Considering the involvement of Akt signalling in a wide variety of cell physiological events, and in many challenging diseases such as type-2 diabetes and cancer, the evidence of a link between cell geometry and Akt signalling could have broader implications and warrants further investigation in other cell systems. Moreover, depending on the soluble factor environment, cell geometry was observed to have different, seemingly antagonistic effects, on cell differentiation. In the absence of soluble differentiation cues, β-catenin was found to mediate cell differentiation in a most likely Wnt independent mechanism. Furthermore, by developing a novel system based on decellularized ECM micropatterns, it was reported that cell architecture also changes ECM structure by cell shape-dependent secretion of ECM proteins, suggesting a bi-directional regulatory mechanism between cell shape and ECM. It was also found that downstream effects caused by other mechanical cues in the cell microenvironment, such as matrix elasticity and topography, are indirect effects mediated by changes in cell geometry. Therefore, cell architecture seems to have an important role in mediating cell physiological effects of ECM and might be a main component that transduces effects of mechanobiological cues into specific downstream behaviour. The work in this thesis suggests a possible key role of cell geometry within the cell microenvironment, and is highly relevant for improved targeted therapies, especially in cancer, the design of tissue engineering scaffolds and in vitro drug screening systems.
Supervisor: Stevens, Molly Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available