Force Propagation in Mammalian Cell Systems and the Relevance of the Mechanically Integrated Cell

Mammalian cells are known to respond to both extra- and intra- cellular forces as well as the physical properties of the surrounding tissue. There is increasing evidence to support the fundamental role of force, applied to or generated within cells, in maintaining proper tissue function. The mechanical integration from the exterior of a cell to the interior of the nucleus is crucial for cellular sensing of, and response to, the physical environment. Further, misregulation of this mechanosensitive ability can lead to the development or propagation of many diseases such as cancers, cardiovascular diseases, and tissue fibrosis. In this thesis, we investigate the role of various proteins in regulating the mechanical properties of mammalian cells. We also develop techniques to examine the propagation of forces through cells and multicell systems with the aim of elucidating critical biophysical factors involved in regulating cell function. The idea that the genome can be regulated through changes in forces applied to cells or changes in the propagation of forces through a cell, (i.e. mechanotransduction) is becoming widely accepted. The complex interplay between biochemical and biophysical mechanisms that ultimately control mechanotransduction are beginning to be uncovered; however, a true understanding of this remarkable cellular process has not yet been achieved. By investigating multiple factors which impact mechanosensitivity (such as protein expression, cell-cell and cell-environment connections, cell generated contractions, and physical connections through the cellular interior), we aim to further the understanding of potential pathways of mechanotransduction. Through novel studies and technological advances, the field of cellular biomechanics will continue to grow as we hope to uncover the physical mechanisms that regulate cell function or lead to disease.