Date of Award

12-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

Dean, Delphine

Abstract

Most tissue-level mechanical models assume homogeneous mechanical properties within a single cell type. However, measurements of cellular mechanical properties show large variability in whole-cell mechanical properties between cells from a single population. This heterogeneity has been observed in many cell populations and with several measurement techniques but the sources are not yet fully understood. Cell mechanical properties are directly related to the composition and organization of the cytoskeleton, which is physically coupled to neighboring cells through adherens junctions and to underlying matrix scaffolds through focal adhesion complexes. As such, we believe that this high level of heterogeneity can be attributed to varying local microenvironment conditions throughout the sample.
To test this hypothesis, cardiomyocytes and vascular smooth muscle cells were cultured under several conditions that limited the variability in their microenvironment. First, cells were cultured on aligned collagen and fibronectin matrices (more uniform extracellular matrix). Next, cell-cell and cell-matrix interactions were limited by using antibodies to N-cadherin and integrin beta1. Finally, these experiments were replicated on gels and under tension conditions to more closely mimic the native cellular microenvironment. Under each of these conditions, cellular viscoelastic mechanical properties were characterized through AFM testing and cellular structure was analyzed through immunofluorescence imaging.
The results of these studies provide insights from a basic science prospective about the impact of the cellular microenvironment on cell behavior. Additionally, researchers may use these results to consider heterogeneity in the cellular microenvironment in vivo, especially in disease conditions where there is often elevated disorganization, and incorporate realistic levels of cellular heterogeneity in tissue-level mechanical models. Such models may help to better understand tissue behavior in both health and disease.

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