Spatial transcriptomics reveals altered communities and drivers of aberrant epithelia and pro-fibrotic fibroblasts in interstitial lung diseases
Interstitial lung diseases (ILD) are characterized by fibrotic scarring of the lung parenchyma with remarkably unfavorable prognosis. Using single-nucleus RNA sequencing and spatial transcriptomics, we generated a comprehensive cellular network of the distal lung and its alterations in fibrosis. Integration with histopathology revealed that the transformation of normal parenchyma into fibrotic tissue is accompanied by ectopic bronchiolization and decellularization. Areas of active fibrosis were characterized by co-localization of pro-fibrotic CTHRC1-hi fibroblasts and aberrant transitional epithelial cells. We modeled this maladaptive differentiation of alveolar epithelial cells using organoids, demonstrating that all three pro-inflammatory ligands present in this pathogenic niche, TGF-β, IL-1β, and TNF-α, are jointly required for their induction. Additionally, we identified a requirement for the transcription factor NFATC4 during myofibroblast differentiation driven by soluble factors or mechanosensing. Collectively, this work identifies essential molecular drivers of the cellular interactions underlying lung fibrosis.
Authors
- Tresa Rani Sarraf
- Åsa Segerstolpe (ORCID: https://orcid.org/0000-0002-3700-9661)
- Shaina W. Twardus
- Rachel S. Knipe (ORCID: https://orcid.org/0000-0002-4337-5748)
- D. B. Graham (ORCID: https://orcid.org/0000-0002-1046-746X)
- Yin P. Hung (ORCID: https://orcid.org/0000-0002-8568-1591)
- Tristan Kooistra (ORCID: https://orcid.org/0000-0001-7843-0631)
- Ingo Ganzleben (ORCID: https://orcid.org/0000-0003-0571-6641)
- Vladislav Pokatayev (ORCID: https://orcid.org/0000-0002-0562-327X)
- Liat Amir-Zilberstein
- Toni Delorey (ORCID: https://orcid.org/0000-0001-6614-3803)
- Jacques Deguine (ORCID: https://orcid.org/0000-0001-9218-3040)
- Alok Jaiswal
- Ramnik J. Xavier
- Crystal Lin
- Katharine E. Black
- Kevin Shannon
- Lida P. Hariri
- Agostinho Carvalho
- Shane P. Murphy
- Hélder N. Bastos
- Rita F. Santos
Institutions
- Broad Institute (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Center for Systems Biology (US)
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- University of Minho (PT)
Publication Details
- Journal
- Cell Genomics
- Published
- 2026-01-22
- DOI
- https://doi.org/10.1016/j.xgen.2025.101066
- Primary Topic
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Ministerio de Economía y Competitividad
- National Institutes of Health
- Klarman Cell Observatory, Broad Institute
- Fundação para a Ciência e a Tecnologia