(157c) Increased Matrix Rigidity Regulates Epithelial-Myofibroblast Transition Via Mrtf-a Signaling

Myofibroblasts mediate normal wound healing and upon chronic activation can contribute to the development of pathological conditions including organ fibrosis. Myofibroblasts can develop from epithelial cells through an epithelial-myofibroblast transition (EMT) during which epithelial cells exhibit drastic morphological changes and upregulate cytoskeletal proteins that enable myofibroblasts to remodel their surrounding microenvironment. Increased matrix rigidity is a hallmark of fibrosis 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 cell shape changes and cytoskeletal reorganization associated with transforming growth factor (TGF)-β induced EMT, with rigid matrices enabling increased cell spreading and stress fiber formation while soft matrices block these morphological changes.  Furthermore, we find that matrix rigidity controls the subcellular localization and activity of myocardin related transcription factor (MRTF)-A which in turn regulates the expression of cytoskeletal proteins that contribute 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.