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Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration

Author

Listed:
  • Andrea Toth

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Paranthaman Kannan

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center)

  • John Snowball

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center)

  • Matthew Kofron

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Joseph A. Wayman

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center)

  • James P. Bridges

    (University of Colorado Anschutz Medical Campus
    Division of Pulmonary and Critical Care Medicine, National Jewish Health)

  • Emily R. Miraldi

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center)

  • Daniel Swarr

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • William J. Zacharias

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

Abstract

Lung epithelial regeneration after acute injury requires coordination cellular coordination to pattern the morphologically complex alveolar gas exchange surface. During adult lung regeneration, Wnt-responsive alveolar epithelial progenitor (AEP) cells, a subset of alveolar type 2 (AT2) cells, proliferate and transition to alveolar type 1 (AT1) cells. Here, we report a refined primary murine alveolar organoid, which recapitulates critical aspects of in vivo regeneration. Paired scRNAseq and scATACseq followed by transcriptional regulatory network (TRN) analysis identified two AT1 transition states driven by distinct regulatory networks controlled in part by differential activity of Nkx2-1. Genetic ablation of Nkx2-1 in AEP-derived organoids was sufficient to cause transition to a proliferative stressed Krt8+ state, and AEP-specific deletion of Nkx2-1 in adult mice led to rapid loss of progenitor state and uncontrolled growth of Krt8+ cells. Together, these data implicate dynamic epigenetic maintenance via Nkx2-1 as central to the control of facultative progenitor activity in AEPs.

Suggested Citation

  • Andrea Toth & Paranthaman Kannan & John Snowball & Matthew Kofron & Joseph A. Wayman & James P. Bridges & Emily R. Miraldi & Daniel Swarr & William J. Zacharias, 2023. "Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44184-0
    DOI: 10.1038/s41467-023-44184-0
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