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
Figure 8
Lineage-traced YTactive AT2 cells express markers of aberrant differentiation in feeder-free organoid culture.
