Yap Is a Driver of Myofibroblast Differentiation in Normal and Diseased Fibroblasts

Dupuytren disease is a fibrotic disorder characterized by contraction of myofibroblastrich cords and nodules in the hands. The Hippo member Yes-associated protein 1 (YAP) is activated by tissue stiffness and the pro-fibrotic transforming growth factor-β1, but its role in cell fibrogenesis is yet unclear. We hypothesized that YAP regulates the differentiation of dermal fibroblasts into highly contractile myofibroblasts and that YAP governs the maintenance of a myofibroblast phenotype in primary Dupuytren cells. Knockdown of YAP in transforming growth factor-β1-stimulated dermal fibroblasts decreased the formation of contractile smooth muscle α-actin stress fibers and the deposition of collagen type I, which are hallmark features of myofibroblasts. Translating our findings to a clinically relevant model, we found that YAP deficiency in Dupuytren disease myofibroblasts resulted in decreased expression of ACTA2, COL1A1, and CCN2 mRNA, but this did not result in decreased protein levels. YAP-deficient Dupuytren myofibroblasts showed decreased contraction of a collagen hydrogel. Finally, we showed that YAP levels and nuclear localization were elevated in affected Dupuytren disease tissue compared with matched control tissue and partly colocalized with smooth muscle α-actin-positive cells. In conclusion, our data show that YAP is a regulator of myofibroblast differentiation and contributes to the maintenance of a synthetic and contractile phenotype, in both transforming growth factor-β1induced myofibroblast differentiation and primary Dupuytren myofibroblasts.