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Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveo...

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Autores principales: Warren, Rachel, Lyu, Handeng, Klinkhammer, Kylie, De Langhe, Stijn P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10208641/
https://www.ncbi.nlm.nih.gov/pubmed/37166104
http://dx.doi.org/10.7554/eLife.85092
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author Warren, Rachel
Lyu, Handeng
Klinkhammer, Kylie
De Langhe, Stijn P
author_facet Warren, Rachel
Lyu, Handeng
Klinkhammer, Kylie
De Langhe, Stijn P
author_sort Warren, Rachel
collection PubMed
description Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates 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 cell stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, the 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.
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spelling pubmed-102086412023-05-25 Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis Warren, Rachel Lyu, Handeng Klinkhammer, Kylie De Langhe, Stijn P eLife Stem Cells and Regenerative Medicine Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates 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 cell stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, the 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. eLife Sciences Publications, Ltd 2023-05-11 /pmc/articles/PMC10208641/ /pubmed/37166104 http://dx.doi.org/10.7554/eLife.85092 Text en © 2023, Warren, Lyu et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Stem Cells and Regenerative Medicine
Warren, Rachel
Lyu, Handeng
Klinkhammer, Kylie
De Langhe, Stijn P
Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis
title Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis
title_full Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis
title_fullStr Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis
title_full_unstemmed Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis
title_short Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis
title_sort hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis
topic Stem Cells and Regenerative Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10208641/
https://www.ncbi.nlm.nih.gov/pubmed/37166104
http://dx.doi.org/10.7554/eLife.85092
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