4.7 Article

Halofuginone regulates keloid fibroblast fibrotic response to TGF- β induction

Journal

BIOMEDICINE & PHARMACOTHERAPY
Volume 135, Issue -, Pages -

Publisher

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2020.111182

Keywords

Halofuginone; Keloid; Myofibroblasts; TGF-β 1; Fibrosis

Funding

  1. CHU Besancon, FRANCE [APICHU] [RCB 2016-A01579-42]
  2. Agence Nationale de la Recherche (ANR) under the program 'Investissements d'Avenir' [ANR11-LABX-0021-LipSTIC]
  3. Region Bourgogne Franche-Comte
  4. Univ. Bourgogne Franche-Comte [Chrysalide 2019 -Projet emergent]

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Keloids are characterized by increased fibrous tissue deposition during abnormal wound healing. Halofuginone (HF) has been shown to inhibit fibrotic processes in keloid fibroblasts, offering a potential therapeutic approach for keloid prevention and management.
Keloids are characterized by increased deposition of fibrous tissue in the skin and subcutaneous tissue following an abnormal wound healing process. Although keloid etiology is yet to be fully understood, fibroblasts are known to be key players in its development. Here we analyze the antifibrotic mechanisms of Halofuginone (HF), a drug reportedly able to inhibit the TGF-beta 1-Smad3 pathway and to attenuate collagen synthesis, in an in-vitro keloid model using patient-derived Keloid Fibroblasts (KFs) isolated from fibrotic tissue collected during the Scar Wars clinical study (NCT NCT03312166). TGF-beta 1 was used as a pro-fibrotic agent to stimulate fibroblasts response under HF treatment. The fibrotic related properties of KFs, including survival, migration, proliferation, myofibroblasts conversion, ECM synthesis and remodeling, were investigated in 2D and 3D cultures. HF at 50 nM concentration impaired KFs proliferation, and decreased TGF-beta 1-induced expression of alpha-SMA and type I pro collagen production. HF treatment also reduced KFs migration, prevented matrix contraction and increased the metallo-proteases/inhibitors (MMP/TIMP) ratio. Overall, HF elicits an anti-fibrotic contrasting the TGF-beta 1 stimulation of KFs, thus supporting its therapeutic use for keloid prevention and management.

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