Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis
Abstract
Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicate that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating 'indeterminate' states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap1 and Wwtr1 (encoding Taz) or Wwtr1 alone in AT2 cells stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, inactivation of only Yap1 in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.
Data availability
sequencing data have been uploaded to Dryad
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Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosisDryad Digital Repository, doi:10.5061/dryad.tdz08kq3d.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (R35 HL161169)
- Stijn PJ De Langhe
National Heart, Lung, and Blood Institute (R01 HL146461)
- Stijn PJ De Langhe
National Heart, Lung, and Blood Institute (R01 HL132156)
- Stijn PJ De Langhe
National Heart, Lung, and Blood Institute (T32 HL105355)
- Rachel Warren
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Paul W Noble, Cedars-Sinai Medical Center, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#A00006342-21) of the Mayo clinic.
Version history
- Received: November 21, 2022
- Preprint posted: November 30, 2022 (view preprint)
- Accepted: May 10, 2023
- Accepted Manuscript published: May 11, 2023 (version 1)
- Version of Record published: May 24, 2023 (version 2)
Copyright
© 2023, Warren et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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