Sustained YAP/TAZ activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling
Isabella P. Gaona, A. Scott McCall, Natalie M. Geis, Arlo C. Colvard, Gianluca T. DiGiovanni, Taylor P. Sherrill, Ujjal K. Singha, David S. Nichols, Ana P. Serezani, Holly E. David, Jean-Philippe Cartailler, Shristi Shrestha, Sergey S. Gutor, Timothy S. Blackwell, Jonathan A. Kropski, Jason J. Gokey
Isabella P. Gaona, A. Scott McCall, Natalie M. Geis, Arlo C. Colvard, Gianluca T. DiGiovanni, Taylor P. Sherrill, Ujjal K. Singha, David S. Nichols, Ana P. Serezani, Holly E. David, Jean-Philippe Cartailler, Shristi Shrestha, Sergey S. Gutor, Timothy S. Blackwell, Jonathan A. Kropski, Jason J. Gokey
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Research Article Cell biology Pulmonology

Sustained YAP/TAZ activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling

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.

Authors

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

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Figure 6

Single-cell ATAC-seq demonstrates altered AT2 cell chromatin accessibility in YTactive bleomycin-injured mouse lungs associated with aberrant transitional cells.

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Single-cell ATAC-seq demonstrates altered AT2 cell chromatin accessibili...
(A and B) UMAPs demonstrating clustering from 17 cell types in mouse lungs (A) and identifying cells recovered from respective genotype and treatment groups from single-nucleus multiome (RNA + ATAC sequencing [ATAC-seq]) of lung tissue from 28 days after bleomycin (B). (C) Volcano plot showing upregulated gene activity from AT2 cells of bleomycin-injured WT (left) and YTactive (right) mice. (D) Single-cell ATAC-seq shows enriched binding sites for open chromatin regions in bleomycin YTactive AT2 cells. The “avg_diff” is the fold change computing the average difference in chromVAR z score after differential testing between WT (left) and YTactive (right) mice.