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

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 Sftpc<sup>C121G</sup> 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 Sftpc<sup>C121G</sup> 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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Publication Details

Journal
Nature Communications
Published
2025-09-30
DOI
https://doi.org/10.1038/s41467-025-63735-1
Citations
6
Primary Topic
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Type
article
Field-Weighted Citation Impact
9.11

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article

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

Kasey Minakin, Willy Roque Barboza, Jeremy Katzen, Micha Sam Brickman Raredon et al.
6 citations
Nature Communications
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
9.11
article

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

Kasey Minakin, Willy Roque Barboza, Jeremy Katzen, Micha Sam Brickman Raredon, Pushpinder Bawa, L. Raposo Rodríguez, Robert K. Nakamoto, Adam Bennett, Darrell N. Kotton, Aditi Murthy, Yaniv Tomer, Feiya Wang, Apoorva Babu, Maria C. Basil, Katrina Chavez, Konstantinos–Dionysios Alysandratos, Dakota L. Jones, Anit Shah, Lauren J. Ayers, Rachna Dherwani, Evan T. Hoffman, A. Lange, Charlotte H. Cooper, Porter E. Dooley
article en
6 citations

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 Sftpc<sup>C121G</sup> 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 Sftpc<sup>C121G</sup> 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.

Nature CommunicationsVol. 16(1)
Boston University (US), Boston Medical Center (US), Yale University (US), Pulmonary and Allergy Associates (US), Penn Center for AIDS Research (US)
Yale University, University of Pennsylvania, School of Medicine, Boston University, National Institutes of Health, Perelman School of Medicine, University of Pennsylvania, National Institute of General Medical Sciences
Openalex Percentile: Top 2%
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
9.11
DOIOpen Access PDFOpenAlex
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