Biophysical Regulation of TGFbeta1-induced epithelial mesenchymal transition
Open Access
- Author:
- O'connor, Joseph William
- Graduate Program:
- Chemical Engineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- October 01, 2015
- Committee Members:
- Esther Winter Gomez, Dissertation Advisor/Co-Advisor
Manish Kumar, Committee Member
Andrew Zydney, Committee Member
Cheng Dong, Committee Member - Keywords:
- epithelial mesenchymal transition
cytoskeleton
cell adhesion
TGFbeta signaling
epigenetics
microcontact printing - Abstract:
- Myofibroblasts are specialized cells that exert large contractile forces to assist in the closure of wounds. Aberrant and chronic activation of myofibroblasts can contribute to the development of pathological conditions including cancer, fibrosis, and the foreign-body response to implanted biomaterials. Myofibroblasts can develop from epithelial cells through an epithelial-mesenchymal transition (EMT) which can be mediated by a combination of the chemical signal transforming growth factor (TGF)-beta1 and mechanical stimuli. During EMT, epithelial cells detach from adjacent cells and acquire an elongated, mesenchymal-like morphology. These phenotypic changes are accompanied by changes in the expression of epithelial and mesenchymal markers including up-regulation of a variety of cytoskeletal associated proteins such as alpha smooth muscle actin (alphaSMA). A better understanding of the mechanistic underpinnings of how cell and tissue level physical properties contribute to EMT in pathological settings is needed. In order to accomplish this goal, we employ a wide-array of molecular biology tools and engineered cell culture platforms. We find that a combination of TGFbeta1 signaling and biophysical cues, such as cell-matrix adhesion, cell-cell interactions, and epigenetic remodeling, regulate the development of myofibroblasts from epithelial cells. Furthermore, we identify myocardin related transcription factor (MRTF)-A as a key mechanosensitive regulator in several of these processes. This dissertation provides insight into how the cellular microenvironment can control EMT and may suggest ways to enhance wound healing or to engineer therapeutic and diagnostic solutions for fibrosis and cancer.