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PCLAF-DREAM drives alveolar cell plasticity for lung regeneration

Author

Listed:
  • Bongjun Kim

    (The University of Texas MD Anderson Cancer Center)

  • Yuanjian Huang

    (The University of Texas MD Anderson Cancer Center)

  • Kyung-Pil Ko

    (The University of Texas MD Anderson Cancer Center)

  • Shengzhe Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Gengyi Zou

    (The University of Texas MD Anderson Cancer Center)

  • Jie Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Moon Jong Kim

    (The University of Texas MD Anderson Cancer Center)

  • Danielle Little

    (The University of Texas MD Anderson Cancer Center)

  • Lisandra Vila Ellis

    (The University of Texas MD Anderson Cancer Center)

  • Margherita Paschini

    (Boston Children’s Hospital)

  • Sohee Jun

    (The University of Texas MD Anderson Cancer Center)

  • Kwon-Sik Park

    (University of Virginia)

  • Jichao Chen

    (The University of Texas MD Anderson Cancer Center)

  • Carla Kim

    (Boston Children’s Hospital)

  • Jae-Il Park

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • Bongjun Kim & Yuanjian Huang & Kyung-Pil Ko & Shengzhe Zhang & Gengyi Zou & Jie Zhang & Moon Jong Kim & Danielle Little & Lisandra Vila Ellis & Margherita Paschini & Sohee Jun & Kwon-Sik Park & Jichao, 2024. "PCLAF-DREAM drives alveolar cell plasticity for lung regeneration," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53330-1
    DOI: 10.1038/s41467-024-53330-1
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