Dysplastic Alveolar Basaloid Cells Provide a Protective Barrier via KRT17-Stratifin Complex during Chronic Fibrosis
- 1Icahn School of Medicine at Mount Sinai
Abstract
Understanding how lung alveolar type 2 (AT2) stem cells respond to chronic profibrotic insults in idiopathic pulmonary fibrosis is critical for developing therapies and determining physiological relevance of maladaptive regeneration. Using integrated snATAC/snRNA-sequencing of human lungs and in vitro models, we mapped distinct AT2 regenerative trajectories: resolvable euplastic repair and persistent dysplastic repair. Spatially restricted ITGB6/TGF{beta}1/SMAD3 signaling drives AT2-to-basaloid dysplasia via direct upregulation of KRT17 and Stratifin. Using murine models of dysplastic repair and a human precision-cut lung slice/stem cell incorporation assay, we show that KRT17 and its interaction with Stratifin are required for AT2 cell flattening, alveolar coverage, and barrier protection. AT2s leverage these mechanisms to re-epithelialize damaged tissue during chronic fibrosis, navigating a delicate balance between preventing further lung damage and driving aberrant epithelial remodeling. Collectively, we identify novel mechanisms governing alveolar metaplasia and its functional relevance, offering crucial insights for therapeutic interventions in fibrotic lung diseases.
Related
- Targeting hypoxia-responsive miR-155-5p and miR-210-3p restores alveolar regeneration and reverses pulmonary fibrosis
- A lactate-HIF1-VDR positive feedback loop drives protective SPP1+ macrophage differentiation to inhibit schistosomiasis induced liver fibrosis
- Exposure to immune stimuli augments alveolar macrophages to acquire neutrophil antimicrobial molecules to prevent bacterial pneumonia
- GM-CSF Programs Alveolar Macrophages to Maintain Pulmonary Lymphocyte Homeostasis
- Ductal myofibroblasts reactivate contractile program to stabilize alveolar architecture during lung regeneration
BibTeX
@misc{sahasrabudhe2026dysplastic,
title = {{Dysplastic Alveolar Basaloid Cells Provide a Protective Barrier via KRT17-Stratifin Complex during Chronic Fibrosis}},
author = {I. R. Sahasrabudhe and X. Ma and S. A. Iantorno and T. Tran and S. Dsouza and C. Sussman and D. Jones and M. Biscotti and I. Cao and J. Katzen and M. C. Basil and J. L. Hook and K.-D. Alysandratos and J. J. Kathiriya},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.17.724675},
url = {https://www.biorxiv.org/content/10.64898/2026.05.17.724675v3},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Dysplastic Alveolar Basaloid Cells Provide a Protective Barrier via KRT17-Stratifin Complex during Chronic Fibrosis
AU - I. R. Sahasrabudhe
AU - X. Ma
AU - S. A. Iantorno
AU - T. Tran
AU - S. Dsouza
AU - C. Sussman
AU - D. Jones
AU - M. Biscotti
AU - I. Cao
AU - J. Katzen
AU - M. C. Basil
AU - J. L. Hook
AU - K.-D. Alysandratos
AU - J. J. Kathiriya
PY - 2026
DA - 2026/05/17
PB - bioRxiv
DO - 10.64898/2026.05.17.724675
UR - https://www.biorxiv.org/content/10.64898/2026.05.17.724675v3
AB - Understanding how lung alveolar type 2 (AT2) stem cells respond to chronic profibrotic insults in idiopathic pulmonary fibrosis is critical for developing therapies and determining physiological relevance of maladaptive regeneration. Using integrated snATAC/snRNA-sequencing of human lungs and in vitro models, we mapped distinct AT2 regenerative trajectories: resolvable euplastic repair and persistent dysplastic repair. Spatially restricted ITGB6/TGF{beta}1/SMAD3 signaling drives AT2-to-basaloid dysplasia via direct upregulation of KRT17 and Stratifin. Using murine models of dysplastic repair and a human precision-cut lung slice/stem cell incorporation assay, we show that KRT17 and its interaction with Stratifin are required for AT2 cell flattening, alveolar coverage, and barrier protection. AT2s leverage these mechanisms to re-epithelialize damaged tissue during chronic fibrosis, navigating a delicate balance between preventing further lung damage and driving aberrant epithelial remodeling. Collectively, we identify novel mechanisms governing alveolar metaplasia and its functional relevance, offering crucial insights for therapeutic interventions in fibrotic lung diseases.
ER -