Keeping fibroblasts in suspense: TAZ mediated signaling activates a context dependent pro-fibrotic phenotype

1 pro-fibrotic phenotype 2 3 4 Bram Piersma, Ruud A. Bank 5 6 1 University of Groningen, University Medical Center Groningen, Department of Pathology and 7 Medical Biology, Matrix Research Group. 8 9 *corresponding author: Ruud A. Bank, [email protected] 10 11 12 Fibrosis in vital organs causes significant morbidity and mortality worldwide. Although our 13 understanding of the cellular and molecular mechanisms underlying fibrosis has grown 14 tremendously over the last decades, effective treatments that halt, reverse, or prevent the 15 pathological accumulation and remodeling of extracellular matrix (ECM) are lacking. Recent 16 advances revealed that ECM stiffening is one of the hallmarks of chronic fibrosis and stiff ECM 17 is thought to be an active player in the development and progression of the disease (6). ECM 18 stiffening can occur through a variety of processes initiated by the culprit of fibrosis: the 19 myofibroblast. First, an imbalance between the production of ECM and activity of ECM20 degrading enzymes shifts the balance toward ECM accumulation. Second, the sheer volume of 21 collagens and other ECM components push out the interstitial fluids that keep tissues hydrated 22 and compliant. Third, stretching of ECM by myofibroblasts renders the ECM less compliant in a 23 process termed strain-stiffening. Finally, collagens and other ECM components become cross24 linked via both enzymatic (LOX family; transglutaminases) and non-enzymatic mechanisms (2). 25 26 Myofibroblasts are connected with the surrounding ECM through specialized macromolecular 27 assemblies (focal adhesions). Multiple signaling cascades have been implicated in the 28 transduction of mechanical cues. The transcriptional co-activators from the Hippo pathway, YAP 29 and TAZ, were found to act as mechanotransducers in epithelial cells. These findings were 30 recently expanded to human fibrosis in the lung, liver, kidney, and palmar fascia, underlining the 31 Articles in PresS. Am J Physiol Cell Physiol (January 4, 2017). doi:10.1152/ajpcell.00362.2016