YAP1 Is a Driver of Myofibroblast Differentiation in Normal and Diseased Fibroblasts
Open accessAbstract
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.
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MKL-1 and YAP/TAZ directly regulate myofibroblast phenotype.
“Both MKL-1 and YAP/TAZ directly regulate myofibroblast phenotype.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [75]
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Cites
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“org revealed that the translation rate of collagen type I depends more on translation than transcription.(28) Finally, YAP1 deficiency increases the expression of Let7 miRNAs, which are known to target collagen transcripts.”
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“…( Figure 6 , Figure 7 ), we considered the possibility that these processes are connected through the fibroblast to myofibroblast transition (FMT), a subtype of EMT in which stressed or injured fibroblasts differentiate into myofibroblasts ( Phan, 2008 ; Piersma et al., 2015 ; Hinz, 2007 ).”
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Self-citation
- Authors
- Piersma, B., de Rond, S., Werker, P. M. N., Boo, S., Hinz, B., van Beuge, M. M., & Bank, R. A.
- Affiliations
- University Medical Center Groningen (NL)
- University of Toronto (CA)
- Corresponding author
- Bank, Ruud A.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 185
- Issue
- 12
- Pages
- 3326-3337
- ISSN
- 0002-9440 (ISSN-L)
- OpenAlex
- W2174788854
- Cited by
- 135
- References
- 6
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 12 · 2023: 15 · 2022: 14 · 2021: 21 · 2020: 8 · 2019: 13 · 2018: 14 · 2017: 8 · 2016: 6 · 2015: 1
- FWCI
- 8.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- Netherlands Institute for Regenerative Medicine (FES0908)
- Canadian Institutes of Health Research (210820, 286920)
- Topics
- Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- YAP, myofibroblast differentiation, Dupuytren's contracture, fibrosis, dermal fibroblasts, TGF-β1, smooth muscle actin, stress fibers, tissue stiffness, Hippo signaling pathway, connective tissue growth factor, ACTA2, COL1A1
- MeSH terms
- YAP-Signaling Proteins, Cell Differentiation, Cells, Cultured, Collagen, Dupuytren Contracture, Humans, Phosphoproteins, Transcription Factors, Adaptor Proteins, Signal Transducing, Transforming Growth Factor beta1, Gene Knockdown Techniques, Myofibroblasts
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