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  3. Aberrant intermediate alveolar epithelial cells promote pathogenic activation of lung fibroblasts in preclinical fibrosis models

Aberrant intermediate alveolar epithelial cells promote pathogenic activation of lung fibroblasts in preclinical fibrosis models

  • Nat Commun. 2025 Sep 30;16(1):8710. doi: 10.1038/s41467-025-63735-1.
Evan T Hoffman # 1,  Anit Shah # 1,  Willy Roque Barboza 1,  Luis R Rodriguez 1,  Rachna Dherwani 1,  Porter E Dooley 2 3,  Kasey Minakin 2 3,  Yaniv Tomer 1,  Lauren J Ayers 2 3,  Dakota Jones 2 3,  Aditi Murthy 1,  Adam Bennett 1,  Ana N Lange 2,  Pushpinder S Bawa 2,  Feiya Wang 2,  Apoorva Babu 4,  Katrina Chavez 1,  Reilly S Nakamoto 1,  Charlotte H Cooper 1,  Maria C Basil 1 4,  Micha Sam Brickman Raredon 5 6 7,  Darrell N Kotton 2 3,  Konstantinos-Dionysios Alysandratos 2 3,  Jeremy Katzen 8 9
Affiliations

Affiliations

  • 1 Pulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA, USA.
  • 3 The Pulmonary Center and Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
  • 4 PENN -CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA.
  • 6 Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA.
  • 7 Program in Translational Biomedicine (PTB), Yale School of Medicine, New Haven, CT, USA.
  • 8 Pulmonary, Allergy, and Critical Care Medicine Division, University of Pennsylvania, Philadelphia, PA, USA. Jeremy.Katzen@pennmedicine.upenn.edu.
  • 9 PENN -CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA, USA. Jeremy.Katzen@pennmedicine.upenn.edu.
  • # Contributed equally.
PMID: 41027873 DOI: 10.1038/s41467-025-63735-1
Abstract

Pulmonary fibrosis (PF) is a progressive disease histologically defined by pathological fibroblasts and epithelial cells. PF lungs contain alveolar type 2 epithelial cells (AT2s) that acquire an aberrant intermediate state phenotype. However, the direct role of these cells in PF and the signals causing them to arise and persist are not fully known. To address this, we harness the SftpcC121G mouse model, where expression of a PF-associated mutation in the AT2-specific surfactant protein C (Sftpc) gene results in AT2 dysfunction and spontaneous lung fibrosis. Here, we identify aberrant intermediate epithelial cells in SftpcC121G lungs that share transcriptional profiles with human PF aberrant basaloid cells and develop a profibrotic interactome with fibroblasts. We develop a sorting method to enrich for these cells, and through ex vivo assays, identify a profibrotic secretome mediated by TGF-β signaling. Coupling this murine model with a newly developed patient-specific induced pluripotent stem cell-derived mutant SFTPC model, we discover that human SFTPC-mutant AT2s express an aberrant basaloid program, and that loss of canonical progenitor signals coupled with TGF-β stimulation causes AT2s to enter this state. We conclude that aberrant intermediate epithelial cells drive pathogenic fibroblast activation, and that reciprocal signaling contributes to their entry into this profibrotic state.

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