A Human Skin Model Recapitulates Systemic Sclerosis Dermal Fibrosis and Identifies COL22A1 as a TGFβ Early Response Gene that Mediates Fibroblast to Myofibroblast Transition

Watanabe, Tomoya; Baker Frost, DeAnna; Mlakar, Logan; Heywood, Jonathan; da Silveira, Willian A.; Hardiman, Gary; Feghali-Bostwick, Carol

Abstract

Systemic sclerosis (SSc) is a complex multi-system autoimmune disease characterized by immune dysregulation, vasculopathy, and organ fibrosis. Skin fibrosis causes high morbidity and impaired quality of life in affected individuals. Animal models do not fully recapitulate the human disease. Thus, there is a critical need to identify ex vivo models for the dermal fibrosis characteristic of SSc. We identified genes regulated by the pro-fibrotic factor TGFβ in human skin maintained in organ culture. The molecular signature of human skin overlapped with that which was identified in SSc patient biopsies, suggesting that this model recapitulates the dermal fibrosis characteristic of the human disease. We further characterized the regulation and functional impact of a previously unreported gene in the setting of dermal fibrosis, COL22A1, and show that silencing COL22A1 significantly reduced TGFβ-induced ACTA2 expression. COL22A1 expression was significantly increased in dermal fibroblasts from patients with SSc. In summary, we identified the molecular fingerprint of TGFβ in human skin and demonstrated that COL22A1 is associated with the pathogenesis of fibrosis in SSc as an early response gene that may have important implications for fibroblast activation. Further, this model will provide a critical tool with direct relevance to human disease to facilitate the assessment of potential therapies for fibrosis.

Citation

Watanabe, T., Baker Frost, D., Mlakar, L., Heywood, J., da Silveira, W. A., Hardiman, G., & Feghali-Bostwick, C. (2019). A Human Skin Model Recapitulates Systemic Sclerosis Dermal Fibrosis and Identifies COL22A1 as a TGFβ Early Response Gene that Mediates Fibroblast to Myofibroblast Transition. Genes, 10(2), Article 75. https://doi.org/10.3390/genes10020075

• Journal Article Type: Article
• Acceptance Date: Jan 14, 2019
• Online Publication Date: Jan 22, 2019
• Publication Date: Jan 22, 2019
• Deposit Date: Oct 25, 2024
• Publicly Available Date: Oct 25, 2024
• Journal: Genes
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 2
• Article Number: 75
• DOI: https://doi.org/10.3390/genes10020075