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

  • bioRxiv. 2025 Jul 18:2025.07.16.665213. doi: 10.1101/2025.07.16.665213.
Isabella P Gaona  1 ,  A Scott McCall  1  2 ,  Natalie M Geis  1 ,  Arlo C Colvard  1 ,  Gianluca T DiGiovanni  1 ,  Taylor P Sherrill  1 ,  Ujjal K Singha  1 ,  David S Nichols  1 ,  Anna P Serezani  1 ,  Holly E David  1 ,  Jean-Philippe Cartailler  3 ,  Shristi Shrestha  3 ,  Sergey S Gutor  4 ,  Timothy S Blackwell  4 ,  Jonathan A Kropski  1  2  5 ,  Jason J Gokey  1
Affiliations
  • 1. Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 2. Department of Veterans Affairs Medical Center, Nashville, TN 37212, USA.
  • 3. Vanderbilt University, Nashville, TN 37232, USA.
  • 4. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 5. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
PMID: 40791334 DOI: 10.1101/2025.07.16.665213
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 expression of YAP/TAZ transcriptional targets compared to donor control lungs. In human lung organoids, pharmacological YAP/TAZ activation resulted in phenotype shifts of AECs into aberrant transitional states. In mice with YAP/Taz activation (YTactive) resulting from deletion of Hippo-kinases Stk3/4 in alveolar-type 2 (AT2) cells, 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 increased 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 PF.

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