Abstract
The spatiotemporal orchestration of stem/progenitor cells is essential for lung regeneration, the failure of which leads to lung disease, including fibrosis. However, the mechanism of alveolar cell plasticity during regeneration remains elusive. We previously found that PCLAF remodels the DREAM complex for cell quiescence exit and cell proliferation. PCLAF is expressed explicitly in pulmonary proliferative cells, along with the DREAM target genes. Pclaf expression and Pclaf-expressing cells were acutely increased upon lung injury. Intriguingly, Pclaf knock-out mice exhibited lung fibrosis resulting from alveolar type I (AT1) cell loss. The single-cell transcriptome and organoid analyses showed that Pclaf-DREAM complex–transactivated gene expression is required for alveolar type II (AT2) cell transition into AT1. Mechanistically, Clic4, transactivated by the Pclaf-DREAM complex, activates TGF-β signaling for AT2-PPCs-AT1 cell lineage trajectory. Furthermore, pharmacological mimicking of the Pclaf-mediated transcriptome markedly increased alveolar regeneration. Our study unveils an unexpected role of the PCLAF-DREAM axis in controlling alveolar cell plasticity for lung regeneration and proposes a viable option for lung fibrosis prevention.
One Sentence Summary PCLAF-DREAM-driven cell plasticity is essential for lung regeneration, pharmacologically manipulated as a preventive strategy for lung fibrosis.
Competing Interest Statement
The authors have declared no competing interest.
