(549g) Cell-Cell Contact Regulates Tgfβ1-Induced Epithelial-Myofibroblast Transition

Myofibroblasts aid in wound healing and upon aberrant and chronic activation they can contribute to the development of pathological conditions including fibrosis and cancer.  Myofibroblasts can develop from epithelial cells through an epithelial-mesenchymal transition (EMT), a process in which epithelial cells lose cell-cell adhesion, exhibit morphological changes, and upregulate the expression of cytoskeletal proteins including alpha smooth muscle actin.  We have recently demonstrated that cell-matrix adhesion and cell shape changes are required for transforming growth factor (TGF)-β1 induced development of myofibroblasts from epithelial cells, as permitting cells to spread promotes the expression of myogenic markers.  Interestingly, studies have found that cell-cell contact modulates cytoskeletal organization and can increase stress fiber formation in some cell types.  Since mechanical tension and cytoskeletal reorganization are crucial for the activation of myofibroblasts, we sought to examine the effect of cell-cell adhesion on myofibroblast activation.  We employed a microfabrication approach to decouple the effects of cell-cell contact and cell-matrix adhesion in TGFβ induction of EMT.  We find that when cell spreading is controlled, cell-cell contact enhances myofibroblast activation when compared to single cells lacking neighbors.  Furthermore, we identify key signaling pathways responsible for promoting increases in myofibroblast development by cell-cell signaling.  Results provide insight into how cell adhesive cues contribute to the development of myofibroblasts from epithelial cells and may suggest approaches to promote wound healing or to prevent fibrosis and cancer.