Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome

Joanna Y. Wang; Sylvia N. Michki; Sneha Sitaraman; Brandon J. Banaschewski; Reshma Jamal; Jason J. Gokey; Susan M. Lin; Jeremy B. Katzen; Maria C. Basil; Edward Cantu; Jonathan A. Kropski; Jarod A. Zepp; David B. Frank; Lisa R. Young

doi:10.1172/jci.insight.183483

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Michki, S. in: JCI | PubMed | Google Scholar

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Sitaraman, S. in: JCI | PubMed | Google Scholar

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Banaschewski, B. in: JCI | PubMed | Google Scholar

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Jamal, R. in: JCI | PubMed | Google Scholar

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Lin, S. in: JCI | PubMed | Google Scholar

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

Find articles by Cantu, E. in: JCI | PubMed | Google Scholar |

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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

¹Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States of America

²Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

³Division of Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, United States of America

⁴Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University, Nashville, United States of America

⁵Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

⁶Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America

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

JCI Insight. https://doi.org/10.1172/jci.insight.183483.
Copyright © 2024, Wang 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 December 19, 2024 - Version history

Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell function was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage tracing and organoid modeling studies demonstrated that HPS AT2 cells were primed to persist in a Krt8⁺ reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are novel mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.

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Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome

Joanna Y. Wang,¹ Sylvia N. Michki,² Sneha Sitaraman,³ Brandon J. Banaschewski,³ Reshma Jamal,³ Jason J. Gokey,⁴ Susan M. Lin,⁵ Jeremy B. Katzen,⁵ Maria C. Basil,⁵ Edward Cantu,⁶ Jonathan A. Kropski,⁴ Jarod A. Zepp,³ David B. Frank,² and Lisa R. Young³

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Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome

Joanna Y. Wang,1 Sylvia N. Michki,2 Sneha Sitaraman,3 Brandon J. Banaschewski,3 Reshma Jamal,3 Jason J. Gokey,4 Susan M. Lin,5 Jeremy B. Katzen,5 Maria C. Basil,5 Edward Cantu,6 Jonathan A. Kropski,4 Jarod A. Zepp,3 David B. Frank,2 and Lisa R. Young3

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Joanna Y. Wang,¹ Sylvia N. Michki,² Sneha Sitaraman,³ Brandon J. Banaschewski,³ Reshma Jamal,³ Jason J. Gokey,⁴ Susan M. Lin,⁵ Jeremy B. Katzen,⁵ Maria C. Basil,⁵ Edward Cantu,⁶ Jonathan A. Kropski,⁴ Jarod A. Zepp,³ David B. Frank,² and Lisa R. Young³