A single chain variable fragment antibody (Tn 64) cognate to fibronectin type III repeats promotes corneal wound healing by inhibiting fibrosis.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 100965259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1705 (Electronic) Linking ISSN: 15675769 NLM ISO Abbreviation: Int Immunopharmacol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam ; New York : Elsevier Science, c2001-
    • Subject Terms:
      Wound Healing*/drug effects ; Fibrosis* ; Single-Chain Antibodies*/pharmacology ; Single-Chain Antibodies*/genetics ; Tenascin*/metabolism ; Tenascin*/genetics ; Tenascin*/immunology ; Fibroblasts*; Humans ; Fibronectins/metabolism ; Fibronectins/genetics ; Animals ; Cornea/pathology ; Cornea/metabolism ; Cells, Cultured ; Fibronectin Type III Domain ; Cell Line
    • Abstract:
      Corneal wound healing requires epithelial reorganization and stromal extracellular matrix (ECM) remodeling, with ECM proteins such as Tenascin C (TnC) regulating and maintaining corneal homeostasis. The N-terminal globular domain and C-terminal fibrinogen-related domains of TnC are separated by epidermal growth factor (EGF)-like repeats, and upto fifteen fibronectin type III domains (Tn fn). Overexpression of Tn fn 1-5 and its splice variants occurs in varied pathologies. We have previously used Tn64 (a single chain variable fragment antibody cognate to Tn fn 1-5) to establish roles of Tn fn 1-5 in fibrotic pathologies such as rheumatoid arthritis and posterior capsular opacification. Here, we show that Tn64 binds to Tn fn repeats 3-5 (which constitute the major site for binding of soluble fibronectin within TnC). Unlike other Tn fn domains, Tn fn 3-5 displays no inhibition of fibronectin matrix assembly. Rather, the Tn fn 3-5 construct is pro-fibrotic and elicits increased expression of fibronectin. We examined corneal epithelial as well as stromal wound healing through Tn64 binding to Tn fn 3-5, using a human corneal epithelial cell (HCEC) line, primary cultures of human corneal fibroblasts (HCFs), and an ex-vivo corneal organ culture model. Tn64 enhanced proliferation and adhesion of corneal epithelial cells, while inhibiting the migration of corneal fibroblasts and myofibroblasts. Tn64 appears to attenuate inflammation through downregulation of TNF-α, prevent corneal fibrosis by limiting fibronectin polymerization, and promote regeneration of corneal epithelia and stroma, suggesting that it could be developed as a therapeutic agent for effective anti-fibrotic corneal wound healing.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Corneal wound healing; Fibronectin type III repeats; Fibrosis; Tenascin-C; scFv antibody
    • Accession Number:
      0 (Single-Chain Antibodies)
      0 (Tenascin)
      0 (Fibronectins)
    • Publication Date:
      Date Created: 20240419 Date Completed: 20240511 Latest Revision: 20240511
    • Publication Date:
      20240512
    • Accession Number:
      10.1016/j.intimp.2024.112029
    • Accession Number:
      38640715