Cell Size and Shape Regulates Epithelial-Myofibroblast Transition

Abstract

Myofibroblasts aid in wound healing and exert large contractile forces in order to assist in wound closure. Aberrant activation of myofibroblasts can lead to the development of pathological conditions including fibrosis, cancer, and the foreign-body response to implanted biomaterials. Myofibroblasts can develop from epithelial cells through an epithelial-mesenchymal transition (EMT). During EMT, epithelial cells loosen attachments to their neighbors and acquire an elongated morphology. These phenotypic changes are accompanied by alterations in gene expression patterns including upregulation of cytoskeletal 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 employ a microcontact printing approach to control cellular shape and we find that permitting cell spreading promotes the increased expression of myofibroblast markers while restricting cell spreading prevents EMT. Furthermore, we find that the subcellular localization of key mechanoresponsive molecules is regulated by cell shape and plays an important role in regulating the expression of cytoskeletal associated proteins. Results provide insight into how mechanical signals can control the development of myofibroblasts and may suggest ways to engineer therapeutic solutions for fibrosis and cancer.