The mechanosensing machinery of hepatic myofibroblasts promotes liver fibrosis

▸ Martin K, Pritchett J, Llewellyn J, et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat Commun 2016;7:12502.

Liver fibrosis is a key feature of all chronic liver diseases. Myofibroblasts are the principal scar-producing cells in the fibrotic liver and most commonly derived from activated hepatic stellate cells (HSCs). The presence of pathological extracellular matrix (ECM) within the liver leads to an increase in liver stiffness, which perpetuates myofibroblast activation and promotes additional ECM deposition. Antifibrotic therapies to break this self-propagating cycle would therefore be appealing. However, the signals that enable myofibroblasts to sense and respond to this pathological microenvironment have not been fully defined. In this study, the authors have identified a key role for integrin-ß1 in myofibroblasts, signalling via the mechanosensitive transcriptional coactivator factor yes-associated protein 1 (YAP-1) and the P21-activated kinases (PAK), in promoting a pro-fibrogenic myofibroblast phenotype. Initial in vitro studies demonstrated that deletion of integrin-ß1 from murine HSCs could both prevent HSCs differentiating into myofibroblasts and induce reversal of some pro-fibrotic features in differentiated myofibroblasts. They proceeded to perform a transcriptional analysis on wild type and integrin-ß1-deleted hepatic myofibroblasts and identified significant gene changes in mechanosensing pathways. In particular, the absence of integrin-ß1 resulted in diminished YAP-1 and PAK-1 expression. They assessed the functional role of these pathways. Verteporfin, which blocks YAP-1 activity, inhibited myofibroblast activation in vitro and reduced fibrosis in both the carbon tetrachloride (CCl₄) and bile duct ligation (BDL) murine models of chronic liver injury. Similarly, inhibition of PAK-1 using 1,1′-dithiodi-2-naphthol, resulted in attenuated myofibroblast activation in vitro and less hepatic fibrosis in both the CCl₄ and BDL murine models. These data suggest that integrin-ß1 signalling, acting via PAK and YAP-1, may underpin the mechanosensing ability of hepatic myofibroblasts and promote …