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WNT5a-ROR Signaling Is Essential for Alveologenesis

WNT5a is a mainly “non-canonical” WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function...

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Autores principales: Li, Changgong, Smith, Susan M, Peinado, Neil, Gao, Feng, Li, Wei, Lee, Matt K, Zhou, Beiyun, Bellusci, Saverio, Pryhuber, Gloria S, Ho, Hsin-Yi Henry, Borok, Zea, Minoo, Parviz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072327/
https://www.ncbi.nlm.nih.gov/pubmed/32046118
http://dx.doi.org/10.3390/cells9020384
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author Li, Changgong
Smith, Susan M
Peinado, Neil
Gao, Feng
Li, Wei
Lee, Matt K
Zhou, Beiyun
Bellusci, Saverio
Pryhuber, Gloria S
Ho, Hsin-Yi Henry
Borok, Zea
Minoo, Parviz
author_facet Li, Changgong
Smith, Susan M
Peinado, Neil
Gao, Feng
Li, Wei
Lee, Matt K
Zhou, Beiyun
Bellusci, Saverio
Pryhuber, Gloria S
Ho, Hsin-Yi Henry
Borok, Zea
Minoo, Parviz
author_sort Li, Changgong
collection PubMed
description WNT5a is a mainly “non-canonical” WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5a(CAG)) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5a(CAG) phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5a(CAG) lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.
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spelling pubmed-70723272020-03-19 WNT5a-ROR Signaling Is Essential for Alveologenesis Li, Changgong Smith, Susan M Peinado, Neil Gao, Feng Li, Wei Lee, Matt K Zhou, Beiyun Bellusci, Saverio Pryhuber, Gloria S Ho, Hsin-Yi Henry Borok, Zea Minoo, Parviz Cells Article WNT5a is a mainly “non-canonical” WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5a(CAG)) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5a(CAG) phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5a(CAG) lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD. MDPI 2020-02-07 /pmc/articles/PMC7072327/ /pubmed/32046118 http://dx.doi.org/10.3390/cells9020384 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Changgong
Smith, Susan M
Peinado, Neil
Gao, Feng
Li, Wei
Lee, Matt K
Zhou, Beiyun
Bellusci, Saverio
Pryhuber, Gloria S
Ho, Hsin-Yi Henry
Borok, Zea
Minoo, Parviz
WNT5a-ROR Signaling Is Essential for Alveologenesis
title WNT5a-ROR Signaling Is Essential for Alveologenesis
title_full WNT5a-ROR Signaling Is Essential for Alveologenesis
title_fullStr WNT5a-ROR Signaling Is Essential for Alveologenesis
title_full_unstemmed WNT5a-ROR Signaling Is Essential for Alveologenesis
title_short WNT5a-ROR Signaling Is Essential for Alveologenesis
title_sort wnt5a-ror signaling is essential for alveologenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072327/
https://www.ncbi.nlm.nih.gov/pubmed/32046118
http://dx.doi.org/10.3390/cells9020384
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