Chronic TGFβ1 Signaling Drives Aberrant Alveolar-Basaloid Metaplasia through a KRT17-Stratifin migratory complex

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Molecular Biology

Background:

• Chronic fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), exhibit abnormal alveolar regeneration.
• Current treatment options for IPF are limited, highlighting the need for novel therapeutic targets.
• Understanding the mechanisms behind aberrant epithelial repair is crucial for developing new treatments.

Purpose of the Study:

• To identify distinct regenerative trajectories of alveolar type 2 (AT2) cells in human lungs.
• To elucidate the molecular mechanisms governing persistent, non-resolving dysplastic repair in fibrotic lung disease.
• To identify potential therapeutic targets for pathological epithelial remodeling in chronic fibrosis.

Main Methods:

• Integrated single nucleus ATAC- and RNA-sequencing on human lung tissue.
• Utilized an in vitro model to study dysplastic epithelial repair.
• Investigated signaling pathways (ITGB6/TGFβ1/SMAD3) in fibrotic lung regions and murine models.

Main Results:

• Identified two AT2 cell regenerative trajectories: euplastic (resolvable) and dysplastic (non-resolving).
• The dysplastic trajectory is regulated by a spatially restricted ITGB6/TGFβ1/SMAD3 signaling axis in IPF lungs.
• SMAD3 directly regulates KRT17 and Stratifin, and TGFβ1 signaling promotes their interaction essential for dysplastic transitional cell (DTC) migration.

Conclusions:

• Defined the molecular regulation of AT2 cell-driven dysplastic regeneration in chronic fibrotic lung diseases.
• The TGFβ1-induced KRT17-Stratifin axis is a key driver of pathological epithelial remodeling in IPF.
• Targeting this axis offers a potential therapeutic strategy to promote euplastic regeneration and treat fibrotic lung disorders.