Fibrosis, a disease that results in loss of organ function, contributes to a significant number of deaths worldwide and sustained fibrotic activation has been suggested to increase the risk of developing cancer in a variety of tissues. Fibrogenesis and tumor progression are regulated in part through the activation and activity of myofibroblasts. Increasing evidence links myofibroblasts found within fibrotic lesions and the tumor microenvironment to a process termed epithelial‐mesenchymal transition (EMT), a phenotypic change in which epithelial cells acquire mesenchymal characteristics. EMT can be stimulated by soluble signals, including transforming growth factor (TGF)‐β, and recent studies have identified a role for mechanical cues in directing EMT. In this review, we describe the role that EMT plays in fibrogenesis and in the progression of cancer, with particular emphasis placed on biophysical signaling mechanisms that control the EMT program. We further describe specific TGFβ‐induced intracellular signaling cascades that are affected by cell‐ and tissue‐level mechanics. Finally, we highlight the implications of mechanical induction of EMT on the development of treatments and targeted intervention strategies for fibrosis and cancer.

Myofibroblasts, specialized cells that play important roles in wound healing and fibrosis, can develop from epithelial cells through an epithelial-mesenchymal transition (EMT). During EMT, epithelial cells detach from neighboring cells and acquire an elongated, mesenchymal-like morphology. These phenotypic changes are accompanied by changes in gene expression patterns including upregulation of a variety of cytoskeletal associated proteins which contribute to the ability of myofibroblasts to exert large contractile forces. Here, the relationship between cell shape and cytoskeletal tension and the expression of cytoskeletal proteins in transforming growth factor (TGF)-β1-induced EMT is determined. We find that culturing cells in conditions which permit cell spreading and increased contractility promotes the increased expression of myofibroblast markers and cytoskeletal associated proteins. In contrast, blocking cell spreading prevents transdifferentiation to the myofibroblast phenotype. Furthermore, we find that cell shape regulates the expression of cytoskeletal proteins by controlling the subcellular localization of myocardin related transcription factor (MRTF)-A. Pharmacological inhibition of cytoskeletal tension or MRTF-A signaling blocks the acquisition of a myofibroblast phenotype in spread cells while overexpression of MRTF-A promotes the expression of cytoskeletal proteins for all cell shapes. These data suggest that cell shape is a critical determinant of myofibroblast development from epithelial cells.

Myofibroblasts mediate normal wound healing and upon chronic activation can contribute to the development of pathological conditions including organ fibrosis and cancer. Myofibroblasts can develop from epithelial cells through an epithelial-mesenchymal transition (EMT) during which epithelial cells exhibit drastic morphological changes and upregulate cytoskeletal associated proteins that enable exertion of large contractile forces and remodeling of the surrounding microenvironment. Increased matrix rigidity is a hallmark of fibrosis and tumor progression and mechanical tension has been identified as a regulator of EMT; however, the mechanisms governing the mechanical regulation of EMT are not completely understood. Here, we find that matrix rigidity regulates transforming growth factor (TGF)-β1-induced EMT, with rigid substrata enabling increased myofibroblast marker expression, cell morphology changes, and cytoskeletal reorganization while soft matrices block these changes. Furthermore, we find that matrix rigidity controls the subcellular localization of myocardin related transcription factor (MRTF)-A, a regulator of cytoskeletal protein expression that contributes to the acquisition of myogenic features during EMT. Results from these studies provide insight into how biophysical cues contribute to myofibroblast development from epithelial cells and may suggest ways to enhance wound healing or to engineer therapeutic solutions for fibrosis and cancer.

Epithelial-mesenchymal transition (EMT) is a physiological process that plays an important role in embryonic development and wound healing and is appropriated during pathological conditions including fibrosis and cancer metastasis. EMT can be initiated by a variety of factors, including transforming growth factor (TGF)-b, and is characterized by loss of epithelial features including cell-cell contacts and apicobasal polarity and acquisition of a motile, mesenchymal phenotype. A key feature of EMT is reorganization of the cytoskeleton and recent studies have elucidated regulation mechanisms governing this process. This review describes changes in gene expression patterns of cytoskeletal associated proteins during TGFb-induced EMT. It further reports TGFbinduced intracellular signaling cascades that regulate cytoskeletal reorganization during EMT. Finally, it highlights how changes in cytoskeletal architecture during EMT can regulate gene expression, thus further promoting EMT progression. V C 2015 Wiley Periodicals, Inc.

During epithelial-mesenchymal transition (EMT) epithelial cells lose cell-cell adhesion, exhibit morphological changes, and upregulate the expression of cytoskeletal proteins. Previous studies have demonstrated that complete disruption of cell-cell contact can promote transforming growth factor (TGF)-β1-induced EMT and the expression of the myofibroblast marker alpha smooth muscle actin (αSMA). Furthermore, increased cell spreading mediates TGFβ1-induced αSMA expression during EMT. Here, we sought to examine how the presence of partial cell-cell contacts impacts EMT. A microfabrication approach was employed to decouple the effects of cell-cell contact and cell-matrix adhesion in TGFβ1-induced EMT. When cell spreading is controlled, the presence of partial cell-cell contacts enhances expression of αSMA. Moreover, cell spreading and intercellular contacts together control the subcellular localization of activated Notch1 and myocardin related transcription factor (MRTF)-A. Knockdown of Notch1 or MRTF-A as well as pharmacological inhibition of these pathways abates the cell-cell contact mediated expression of αSMA. These data suggest that the interplay between cell-matrix adhesion and intercellular adhesion is an important determinant for some aspects of TGFβ1-induced EMT.