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ResearchIn-Press PreviewCell biologyPulmonology Open Access | 10.1172/jci.insight.198113

Sustained Yap/Taz activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling

Isabella P. Gaona,1 A. Scott McCall,1 Natalie M. Geis,1 Arlo C. Colvard,1 Gianluca T. DiGiovanni,1 Taylor P. Sherrill,1 Ujjal K. Singha,1 David S. Nichols,1 Ana P. Serezani,1 Holly E. David,1 Jean-Philippe Cartailler,2 Shristi Shrestha,2 Sergey S. Gutor,3 Timothy S. Blackwell,3 Jonathan A. Kropski,1 and Jason J. Gokey1

1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

Find articles by Blackwell, T. in: PubMed | Google Scholar

1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of M, Vanderbilt University Medical Center, Nashville, United States of America

2Creative Data Solutions, Center for Stem Cell Biology, Vanderbilt University, Nashville, United States of America

3Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, United States of America

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

Published June 9, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.198113.
Copyright © 2026, Gaona 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 June 9, 2026 - Version history
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Abstract

YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human AEC organoids and in murine AT2 cell organoids generated with genetic YAP/TAZ activation (YTactive) (via deletion of Hippo-kinases Stk3/4), resulted in phenotype shifts into aberrant transitional and airway-like states. Bleomycin injury of YTactive mice resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of YAP/TAZ using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including restored Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained YAP/TAZ activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent YAP/TAZ activity promotes adaptive repair and has potential as a therapeutic strategy for pulmonary fibrosis.

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Version history
  • Version 1 (June 9, 2026): In-Press Preview
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