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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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101551097 Publication Model: Electronic Cited Medium: Print ISSN: 2073-4425 (Print) Linking ISSN: 20734425 NLM ISO Abbreviation: Genes (Basel) Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel : MDPI
    • Subject Terms:
      Collagen/*metabolism ; Myofibroblasts/*metabolism ; Scleroderma, Systemic/*metabolism; Actins/genetics ; Actins/metabolism ; Cells, Cultured ; Collagen/genetics ; Fibrosis ; Humans ; Myofibroblasts/drug effects ; Myofibroblasts/pathology ; Scleroderma, Systemic/genetics ; Scleroderma, Systemic/pathology ; Skin/metabolism ; Skin/pathology ; Transforming Growth Factor beta/pharmacology
    • 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.
      Competing Interests: The authors declare no conflict of interest.
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    • Grant Information:
      KL2TR001452 United States NH NIH HHS; UL1TR001450 United States NH NIH HHS; KL2 TR001452 United States TR NCATS NIH HHS; K24AR060297 United States NH NIH HHS; K24 AR060297 United States AR NIAMS NIH HHS; UL1 TR001450 United States TR NCATS NIH HHS
    • Contributed Indexing:
      Keywords: COL22A1; TGF; fibroblasts; fibrosis; systemic sclerosis
    • Accession Number:
      0 (ACTA2 protein, human)
      0 (Actins)
      0 (COL22A1 protein, human)
      0 (Transforming Growth Factor beta)
      9007-34-5 (Collagen)
    • Publication Date:
      Date Created: 20190126 Date Completed: 20191111 Latest Revision: 20200309
    • Publication Date:
      20231215
    • Accession Number:
      PMC6409682
    • Accession Number:
      10.3390/genes10020075
    • Accession Number:
      30678304