title: YAP1 Is a Driver of Myofibroblast Differentiation in Normal and Diseased Fibroblasts.
abstract: Dupuytren disease is a fibrotic disorder characterized by contraction of myofibroblast-rich cords and nodules in the hands. The Hippo member Yes-associated protein 1 (YAP1) is activated by tissue stiffness and the profibrotic transforming growth factor-β1, but its role in cell fibrogenesis is yet unclear. We hypothesized that YAP1 regulates the differentiation of dermal fibroblasts into highly contractile myofibroblasts and that YAP1 governs the maintenance of a myofibroblast phenotype in primary Dupuytren cells. Knockdown of YAP1 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 YAP1 deficiency in Dupuytren disease myofibroblasts resulted in decreased expression of ACTA2, COL1A1, and CCN2 mRNA, but this did not result in decreased protein levels. YAP1-deficient Dupuytren myofibroblasts showed decreased contraction of a collagen hydrogel. Finally, we showed that YAP1 levels and nuclear localization were elevated in affected Dupuytren disease tissue compared with matched control tissue and partly co-localized with smooth muscle α-actin-positive cells. In conclusion, our data show that YAP1 is a regulator of myofibroblast differentiation and contributes to the maintenance of a synthetic and contractile phenotype, in both transforming growth factor-β1-induced myofibroblast differentiation and primary Dupuytren myofibroblasts.
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Matrix Research Group, Groningen, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: Piersma
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Matrix Research Group, Groningen, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: de Rond
authors.affiliation: Department of Plastic Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Paul M N
authors.initials: PM
authors.lastname: Werker
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stellar
authors.initials: S
authors.lastname: Boo
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Matrix Research Group, Groningen, The Netherlands.
authors.forename: Marike M
authors.initials: MM
authors.lastname: van Beuge
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Matrix Research Group, Groningen, The Netherlands. Electronic address: r.a.bank@umcg.nl.
authors.forename: Ruud A
authors.initials: RA
authors.lastname: Bank
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004387:Dupuytren Contracture / Q000378:metabolism / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D003094:Collagen