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

Evan T. Hoffman, Anit Shah, Willy Roque Barboza, Luis R. Rodriguez, Rachna Dherwani, Porter E. Dooley, Kasey Minakin, Yaniv Tomer, Lauren J. Ayers, Dakota Jones, Aditi Murthy, Adam Bennett, Ana N. Lange, Pushpinder S. Bawa, Feiya Wang, Apoorva Babu, Katrina Chavez, Reilly S. Nakamoto, Charlotte H. Cooper, Maria C. Basil, Micha Sam Brickman Raredon, Darrell N. Kotton, Konstantinos-Dionysios Alysandratos and Jeremy Katzen ()
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Evan T. Hoffman: University of Pennsylvania
Anit Shah: University of Pennsylvania
Willy Roque Barboza: University of Pennsylvania
Luis R. Rodriguez: University of Pennsylvania
Rachna Dherwani: University of Pennsylvania
Porter E. Dooley: Boston University and Boston Medical Center
Kasey Minakin: Boston University and Boston Medical Center
Yaniv Tomer: University of Pennsylvania
Lauren J. Ayers: Boston University and Boston Medical Center
Dakota Jones: Boston University and Boston Medical Center
Aditi Murthy: University of Pennsylvania
Adam Bennett: University of Pennsylvania
Ana N. Lange: Boston University and Boston Medical Center
Pushpinder S. Bawa: Boston University and Boston Medical Center
Feiya Wang: Boston University and Boston Medical Center
Apoorva Babu: University of Pennsylvania
Katrina Chavez: University of Pennsylvania
Reilly S. Nakamoto: University of Pennsylvania
Charlotte H. Cooper: University of Pennsylvania
Maria C. Basil: University of Pennsylvania
Micha Sam Brickman Raredon: Yale School of Medicine
Darrell N. Kotton: Boston University and Boston Medical Center
Konstantinos-Dionysios Alysandratos: Boston University and Boston Medical Center
Jeremy Katzen: University of Pennsylvania

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63735-1

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