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ResearchIn-Press PreviewCell biologyPulmonology Open Access | 10.1172/jci.insight.159331

Hypercapnia alters stromal-derived Wnt production limiting β-catenin signaling and proliferation in alveolar type 2 cells

Laura A. Dada,1 Lynn C. Welch,1 Natalia D. Magnani,1 Ziyou Ren,1 Hyebin Han,1 Patricia L. Brazee,1 Diego Celli,1 Annette S. Flozak,1 Anthea Weng,1 Mariana Maciel Herrerias,1 Vitalii Kryvenko,2 István Vadász,2 Constance E. Runyan,1 Hiam Abdala-Valencia,1 Masahiko Shigemura,1 S. Marina Casalino-Matsuda,1 Alexander V. Misharin,1 G.R. Scott Budinger,1 Cara J. Gottardi,1 and Jacob I. Sznajder1

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Dada, L. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Welch, L. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Magnani, N. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Ren, Z. in: JCI | PubMed | Google Scholar

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Han, H. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Brazee, P. in: JCI | PubMed | Google Scholar

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Celli, D. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Flozak, A. in: JCI | PubMed | Google Scholar

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Weng, A. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Herrerias, M. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Kryvenko, V. in: JCI | PubMed | Google Scholar

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Vadász, I. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Runyan, C. in: JCI | PubMed | Google Scholar

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Abdala-Valencia, H. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Shigemura, M. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Casalino-Matsuda, S. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Misharin, A. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Budinger, G. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Gottardi, C. in: JCI | PubMed | Google Scholar |

1Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America

2Department of Internal Medicine, Universities of Giessen & Marburg Lung Center, Giessen, Germany

Find articles by Sznajder, J. in: JCI | PubMed | Google Scholar

Published January 10, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.159331.
Copyright © 2023, Dada et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 10, 2023 - Version history
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Abstract

Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with ARDS secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here, using a mouse model of hypercapnia exposure, cell lineage-tracing, spatial transcriptomics and 3D-cultures, we show that hypercapnia limits β-catenin signaling in AT2 cells, leading to their reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRα+-fibroblasts from those maintaining AT2 progenitor activity towards those that antagonize β-catenin signaling thereby limiting progenitor function. Constitutive activation of β-catenin signaling in AT2 cells or treatment of organoid cultures with recombinant WNT3A protein bypasses the inhibitory effects of hypercapnia. Inhibition of AT2 proliferation in hypercapnic patients may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier, increasing lung flooding, ventilator dependency and mortality.  

Graphical Abstract
graphical abstract
Version history
  • Version 1 (January 10, 2023): In-Press Preview
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