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

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Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St, MSC 637, Charleston, SC 29425, USA
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Center for Genomic Medicine, Bioinformatics, Medical University of South Carolina, Charleston, SC 29425, USA
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Departments of Medicine and Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
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School of Biological Sciences & Institute for Global Food Security, Queens University Belfast, Belfast BT9 5AG, UK
*
Author to whom correspondence should be addressed.
Genes 2019, 10(2), 75; https://doi.org/10.3390/genes10020075
Received: 10 December 2018 / Accepted: 14 January 2019 / Published: 22 January 2019
(This article belongs to the Section Human Genomics and Genetic Diseases)
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. View Full-Text
Keywords: fibrosis; systemic sclerosis; COL22A1; fibroblasts; TGF fibrosis; systemic sclerosis; COL22A1; fibroblasts; TGF
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Watanabe, T.; Baker Frost, D.; Mlakar, L.; Heywood, J.; da Silveira, W.A.; Hardiman, G.; Feghali-Bostwick, C. 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 2019, 10, 75.

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