Your browser doesn't support javascript.
loading
A fibroblast-dependent TGF-ß1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis.
Cohen, Max L; Brumwell, Alexis N; Ho, Tsung Che; Garakani, Kiana; Montas, Genevieve; Leong, Darren; Ding, Vivianne W; Golden, Jeffrey A; Trinh, Binh N; Jablons, David M; Matthay, Michael A; Jones, Kirk D; Wolters, Paul J; Wei, Ying; Chapman, Harold A; Le Saux, Claude Jourdan.
Afiliación
  • Cohen ML; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Brumwell AN; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Ho TC; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Garakani K; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Montas G; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Leong D; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Ding VW; Department of Surgery, Division of Cardiothoracic Surgery, and.
  • Golden JA; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Trinh BN; Department of Surgery, Division of Cardiothoracic Surgery, and.
  • Jablons DM; Department of Surgery, Division of Cardiothoracic Surgery, and.
  • Matthay MA; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Jones KD; Department of Pathology, University of California San Francisco, San Francisco, California, USA.
  • Wolters PJ; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Wei Y; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Chapman HA; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
  • Le Saux CJ; Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine.
J Clin Invest ; 134(18)2024 Jul 09.
Article en En | MEDLINE | ID: mdl-38980870
ABSTRACT
Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGF-ß1 signaling inhibitor epigallocatechin gallate (EGCG) to interstitial lung disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA-Seq on spare tissue. Biopsies from untreated patients showed higher fibroblast TGF-ß1 signaling compared with nondisease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGF-ß1 signaling and several proinflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzled-related protein 2 (sFRP2), an unrecognized TGF-ß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision-cut lung slices (PCLSs) from nondiseased donors, we found TGF-ß1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature cytokeratin 5+ (Krt5+) basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGF-ß1 signaling in ILD and the therapeutic potential of EGCG in reducing idiopathic pulmonary fibrosis-related (IPF-related) transcriptional changes and identify TGF-ß1/noncanonical Wnt pathway crosstalk via sFRP2 as a mechanism for dysfunctional epithelial signaling in IPF/ILD.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta1 / Fibrosis Pulmonar Idiopática / Vía de Señalización Wnt / Fibroblastos / Metaplasia Límite: Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factor de Crecimiento Transformador beta1 / Fibrosis Pulmonar Idiopática / Vía de Señalización Wnt / Fibroblastos / Metaplasia Límite: Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Clin Invest Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos