Date of Award
12-22-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The cell is a sophisticated machine, integrating chemical and physical inputs to decide upon the mechanobiological outputs that the body requires every second, in cardiomyocytes that make heartbeats, in fibroblasts that heal wounds, and in sarcomeres that contract muscles. Malfunction of mechanotransduction or mechanical inputs is implicated in diseases such as fibrosis, cancers, and cardiomyopathies, and a pressing quest is underway to unravel the intricacies of how mechanical force orchestrates the activation of cells. This dissertation explores these fundamental mechanisms of cell activation using integrated mathematical and engineered cell culture models. The work begins with the discovery that the directionality of mechanical tension is a dominant factor in fibroblast polarization, contractility, and transformation into pro-fibrotic phenotypes. The dissertation describes a self-reinforcing feedback loop underlying this, with local ECM fiber alignment patterns directing tension anisotropy through cell protrusions, which further activates cells. The dissertation then shows that ECM viscoelasticity interacts with cell mechanobiology to determine these outcomes, with sufficiently large stretch sometimes inducing less mechanical memory in cells than smaller stretch in a three-dimensional environment. Finally, the dissertation shows that the intermediate filament vimentin is a key regulator of cell polarization and contractility due to its role in stabilizing force-bearing protrusions. This integrated experimental and computational research advances understanding of how cells integrate and respond to multidirectional mechanical signals across length- and time-scales. By defining fundamental mechanisms of cell activation, these findings establish new quantitative frameworks to direct cell mechanical plasticity in wound healing, disease intervention, regenerative medicine, skin grafting, and mechanotherapy.
Language
English (en)
Chair
Guy Genin