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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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    as
    1. Rogan A. Grant & Luisa Morales-Nebreda & Nikolay S. Markov & Suchitra Swaminathan & Melissa Querrey & Estefany R. Guzman & Darryl A. Abbott & Helen K. Donnelly & Alvaro Donayre & Isaac A. Goldberg & Z, 2021. "Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia," Nature, Nature, vol. 590(7847), pages 635-641, February.
    2. Lu Han & Praneet Chaturvedi & Keishi Kishimoto & Hiroyuki Koike & Talia Nasr & Kentaro Iwasawa & Kirsten Giesbrecht & Phillip C. Witcher & Alexandra Eicher & Lauren Haines & Yarim Lee & John M. Shanno, 2020. "Single cell transcriptomics identifies a signaling network coordinating endoderm and mesoderm diversification during foregut organogenesis," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    3. Ameen A. Salahudeen & Shannon S. Choi & Arjun Rustagi & Junjie Zhu & Vincent Unen & Sean M. O & Ryan A. Flynn & Mar Margalef-Català & António J. M. Santos & Jihang Ju & Arpit Batish & Tatsuya Usui & G, 2020. "Progenitor identification and SARS-CoV-2 infection in human distal lung organoids," Nature, Nature, vol. 588(7839), pages 670-675, December.
    4. Minzhe Guo & Yina Du & Jason J. Gokey & Samriddha Ray & Sheila M. Bell & Mike Adam & Parvathi Sudha & Anne Karina Perl & Hitesh Deshmukh & S. Steven Potter & Jeffrey A. Whitsett & Yan Xu, 2019. "Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    5. William J. Zacharias & David B. Frank & Jarod A. Zepp & Michael P. Morley & Farrah A. Alkhaleel & Jun Kong & Su Zhou & Edward Cantu & Edward E. Morrisey, 2018. "Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor," Nature, Nature, vol. 555(7695), pages 251-255, March.
    6. Kyle J. Travaglini & Ahmad N. Nabhan & Lolita Penland & Rahul Sinha & Astrid Gillich & Rene V. Sit & Stephen Chang & Stephanie D. Conley & Yasuo Mori & Jun Seita & Gerald J. Berry & Joseph B. Shrager , 2020. "A molecular cell atlas of the human lung from single-cell RNA sequencing," Nature, Nature, vol. 587(7835), pages 619-625, November.
    7. Maximilian Strunz & Lukas M. Simon & Meshal Ansari & Jaymin J. Kathiriya & Ilias Angelidis & Christoph H. Mayr & George Tsidiridis & Marius Lange & Laura F. Mattner & Min Yee & Paulina Ogar & Arunima , 2020. "Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    8. Rajan Jain & Christina E. Barkauskas & Norifumi Takeda & Emily J. Bowie & Haig Aghajanian & Qiaohong Wang & Arun Padmanabhan & Lauren J. Manderfield & Mudit Gupta & Deqiang Li & Li Li & Chinmay M. Tri, 2015. "Plasticity of Hopx+ type I alveolar cells to regenerate type II cells in the lung," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    9. Danielle R. Little & Anne M. Lynch & Yun Yan & Haruhiko Akiyama & Shioko Kimura & Jichao Chen, 2021. "Differential chromatin binding of the lung lineage transcription factor NKX2-1 resolves opposing murine alveolar cell fates in vivo," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    10. Suoqin Jin & Christian F. Guerrero-Juarez & Lihua Zhang & Ivan Chang & Raul Ramos & Chen-Hsiang Kuan & Peggy Myung & Maksim V. Plikus & Qing Nie, 2021. "Inference and analysis of cell-cell communication using CellChat," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
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