Faculty, Staff and Student Publications
Publication Date
10-24-2024
Journal
Nature Communications
Abstract
Cell plasticity, changes in cell fate, is crucial for tissue regeneration. In the lung, failure of regeneration leads to diseases, including fibrosis. However, the mechanisms governing alveolar cell plasticity during lung repair remain elusive. We previously showed that PCLAF remodels the DREAM complex, shifting the balance from cell quiescence towards cell proliferation. Here, we find that PCLAF expression is specific to proliferating lung progenitor cells, along with the DREAM target genes transactivated by lung injury. Genetic ablation of Pclaf impairs AT1 cell repopulation from AT2 cells, leading to lung fibrosis. Mechanistically, the PCLAF-DREAM complex transactivates CLIC4, triggering TGF-β signaling activation, which promotes AT1 cell generation from AT2 cells. Furthermore, phenelzine that mimics the PCLAF-DREAM transcriptional signature increases AT2 cell plasticity, preventing lung fibrosis in organoids and mice. Our study reveals the unexpected role of the PCLAF-DREAM axis in promoting alveolar cell plasticity, beyond cell proliferation control, proposing a potential therapeutic avenue for lung fibrosis prevention.
Keywords
Animals, Regeneration, Mice, Cell Plasticity, Alveolar Epithelial Cells, Cell Proliferation, Lung, Chloride Channels, Mice, Inbred C57BL, Transforming Growth Factor beta, Lung Injury, Pulmonary Fibrosis, Signal Transduction, Humans, Mice, Knockout, Male
DOI
10.1038/s41467-024-53330-1
PMID
39448571
PMCID
PMC11502753
PubMedCentral® Posted Date
10-24-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons