Cargando…
Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia
Background: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR in BPD...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226730/ https://www.ncbi.nlm.nih.gov/pubmed/32252341 http://dx.doi.org/10.3390/cells9040859 |
_version_ | 1783534348370182144 |
---|---|
author | Chao, Cho-Ming Carraro, Gianni Rako, Zvonimir A. Kolck, Johannes Sedighi, Jamschid Zimmermann, Volker Moiseenko, Alena Wilhelm, Jochen Young, Brittany M. Chong, Lei Wu, Jin Contreras, Adriana Minoo, Parviz Barreto, Guillermo Warburton, David Bellusci, Saverio |
author_facet | Chao, Cho-Ming Carraro, Gianni Rako, Zvonimir A. Kolck, Johannes Sedighi, Jamschid Zimmermann, Volker Moiseenko, Alena Wilhelm, Jochen Young, Brittany M. Chong, Lei Wu, Jin Contreras, Adriana Minoo, Parviz Barreto, Guillermo Warburton, David Bellusci, Saverio |
author_sort | Chao, Cho-Ming |
collection | PubMed |
description | Background: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR in BPD, a causal role remains to be established. Results: Our results showed that the expression level of miR-154 increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of miR-154 in alveolar type 2 cells (AT2). We hypothesized that the decrease in miR-154 expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based miR-154 overexpression. Maintenance of miR-154 expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified Caveolin1 as a key downstream target of miR-154. Caveolin1 protein is downregulated in response to overexpression of miR-154. This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing miR-154 display decreased expression of AT2 markers and increased expression of AT1 markers. Conclusion: Our results suggest that down-regulation of miR-154 in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate miR-154 suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification. |
format | Online Article Text |
id | pubmed-7226730 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72267302020-05-18 Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia Chao, Cho-Ming Carraro, Gianni Rako, Zvonimir A. Kolck, Johannes Sedighi, Jamschid Zimmermann, Volker Moiseenko, Alena Wilhelm, Jochen Young, Brittany M. Chong, Lei Wu, Jin Contreras, Adriana Minoo, Parviz Barreto, Guillermo Warburton, David Bellusci, Saverio Cells Article Background: Bronchopulmonary dysplasia (BPD) is a lung disease of preterm born infants, characterized by alveolar simplification. MicroRNA (miR) are known to be involved in many biological and pathological processes in the lung. Although a changed expression has been described for several miR in BPD, a causal role remains to be established. Results: Our results showed that the expression level of miR-154 increases during lung development and decreases postnatally. Further, hyperoxia treatment maintains high levels of miR-154 in alveolar type 2 cells (AT2). We hypothesized that the decrease in miR-154 expression in AT2 cells is required for normal alveologenesis. To test this hypothesis, we generated a novel transgenic mouse allowing doxycycline-based miR-154 overexpression. Maintenance of miR-154 expression in the postnatal distal lung epithelium under normoxia conditions is sufficient to reproduce the hypoalveologenesis phenotype triggered by hyperoxia. Using a pull-down assay, we identified Caveolin1 as a key downstream target of miR-154. Caveolin1 protein is downregulated in response to overexpression of miR-154. This is associated with increased phosphorylation of Smad3 and Tgf-ß signaling. We found that AT2 cells overexpressing miR-154 display decreased expression of AT2 markers and increased expression of AT1 markers. Conclusion: Our results suggest that down-regulation of miR-154 in postnatal lung may function as an important physiological switch that permits the induction of the correct alveolar developmental program, while conversely, failure to down-regulate miR-154 suppresses alveolarization, leading to the common clinically observed phenotype of alveolar simplification. MDPI 2020-04-02 /pmc/articles/PMC7226730/ /pubmed/32252341 http://dx.doi.org/10.3390/cells9040859 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 Chao, Cho-Ming Carraro, Gianni Rako, Zvonimir A. Kolck, Johannes Sedighi, Jamschid Zimmermann, Volker Moiseenko, Alena Wilhelm, Jochen Young, Brittany M. Chong, Lei Wu, Jin Contreras, Adriana Minoo, Parviz Barreto, Guillermo Warburton, David Bellusci, Saverio Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia |
title | Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia |
title_full | Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia |
title_fullStr | Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia |
title_full_unstemmed | Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia |
title_short | Failure to Down-Regulate miR-154 Expression in Early Postnatal Mouse Lung Epithelium Suppresses Alveologenesis, with Changes in Tgf-β Signaling Similar to those Induced by Exposure to Hyperoxia |
title_sort | failure to down-regulate mir-154 expression in early postnatal mouse lung epithelium suppresses alveologenesis, with changes in tgf-β signaling similar to those induced by exposure to hyperoxia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226730/ https://www.ncbi.nlm.nih.gov/pubmed/32252341 http://dx.doi.org/10.3390/cells9040859 |
work_keys_str_mv | AT chaochoming failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT carrarogianni failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT rakozvonimira failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT kolckjohannes failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT sedighijamschid failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT zimmermannvolker failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT moiseenkoalena failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT wilhelmjochen failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT youngbrittanym failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT chonglei failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT wujin failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT contrerasadriana failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT minooparviz failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT barretoguillermo failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT warburtondavid failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia AT belluscisaverio failuretodownregulatemir154expressioninearlypostnatalmouselungepitheliumsuppressesalveologenesiswithchangesintgfbsignalingsimilartothoseinducedbyexposuretohyperoxia |