Clu⁺ transitional alveolar epithelial cells promote lung injury repair and fibrosis progression

Idiopathic pulmonary fibrosis is an irreversible disease characterized by progressive inflammation and extracellular matrix deposition, leading to compromised lung function and structural damage. Despite advances in understanding the pathology of pulmonary fibrosis, the role of transitional cell populations in the progression from inflammation to fibrosis is still not well understood.

This study investigates an intermediate subpopulation of alveolar epithelial cells, termed "Regeneration Alveolar Epithelial cells" (RAEs), which reach a peak 14 days post-injury. RAEs are identified through single-cell RNA sequencing of lung injury and development datasets. We characterize RAEs by analysing cross-species datasets and employing experimental approaches, including immunofluorescence staining, immunoblotting, and haematoxylin-eosin staining in mouse models, along with functional assays in human MRC-5 cells.

Marked by Clu, Igfbp6, and Krt19, RAEs represent a transitional state between AT2 and AT1 cells and interact with activated fibroblasts to modulate extracellular matrix secretion. Clu knockdown exacerbated inflammation and fibrosis, while RAEs accumulated in human fibrotic tissues, correlating with impaired lung function and poor prognosis. Functional assays further reveal that CLU⁺ epithelial cells enhanced fibroblast migration and proliferation.

These findings suggest RAEs may play important roles in lung repair processes and in the progression from lung injury to fibrosis.