Sustained YAP/TAZ activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling
8 affiliations
- 1Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- 2Department of Veterans Affairs Medical Center, Nashville, TN 37212, USA
- 3Department of Veterans Affairs Medical Center, Nashville, TN 371, USA
- 4Vanderbilt University, Nashville, TN 37232, USA
- 5Vanderbilt University, Nashville, TN 722, USA
- 6Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
- 7Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 8109, USA
- 8Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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. We investigated whether persistent YAP/TAZ alveolar epithelial cell signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+TAZ+ alveolar epithelial cells and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human alveolar epithelial cell organoids and in murine AT2 cell organoids generated with genetic YAP/TAZ activation (YTactive) (via deletion of Hippo kinases Stk3 and Stk4) 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 after 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 after 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 that 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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BibTeX
@article{gaona2026sustained,
title = {{Sustained YAP/TAZ activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling}},
author = {Isabella P. Gaona and A. Scott McCall and Natalie M. Geis and Arlo C. Colvard and Gianluca T. DiGiovanni and Taylor P. Sherrill and Ujjal K. Singha and David S. Nichols and Ana Paula Moreira Serezani and Holly E. David and Jean‐Philippe Cartailler and Shristi Shrestha and Sergey S Gutor and Timothy S. Blackwell and Jonathan A. Kropski and Jason J. Gokey},
journal = {JCI Insight},
year = {2026},
month = jun,
doi = {10.1172/jci.insight.198113},
url = {https://doi.org/10.1172/jci.insight.198113},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sustained YAP/TAZ activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling
AU - Isabella P. Gaona
AU - A. Scott McCall
AU - Natalie M. Geis
AU - Arlo C. Colvard
AU - Gianluca T. DiGiovanni
AU - Taylor P. Sherrill
AU - Ujjal K. Singha
AU - David S. Nichols
AU - Ana Paula Moreira Serezani
AU - Holly E. David
AU - Jean‐Philippe Cartailler
AU - Shristi Shrestha
AU - Sergey S Gutor
AU - Timothy S. Blackwell
AU - Jonathan A. Kropski
AU - Jason J. Gokey
PY - 2026
DA - 2026/06/09
JO - JCI Insight
DO - 10.1172/jci.insight.198113
UR - https://doi.org/10.1172/jci.insight.198113
AB - 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. We investigated whether persistent YAP/TAZ alveolar epithelial cell signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+TAZ+ alveolar epithelial cells and increased transcriptional target expression. Pharmacological YAP/TAZ activation in human alveolar epithelial cell organoids and in murine AT2 cell organoids generated with genetic YAP/TAZ activation (YTactive) (via deletion of Hippo kinases Stk3 and Stk4) 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 after 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 after 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 that 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.
SN - 2379-3708
ER -