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Article

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

1
Key laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
2
Cardio-Pulmonary Institute and Institute for Lung Health, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany
3
Division of General Pediatrics and Neonatology, University Children’s Hospital Gießen, Justus-Liebig-University, 35392 Giessen, Germany
4
Cedars-Sinai Medical Center, Lung and Regenerative Medicine Institutes, Department of Medicine, Los Angeles, CA, 90027, USA
5
Department of Neurology, University of California, Los Angeles, CA 90095, USA
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Institute of Pediatrics, Discipline of Pediatric Respiratory Medicine, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China
7
College of Life and Environmental Sciences, Wenzhou University, Wenzhou 325027, Zhejiang, China
8
Lung Cancer Epigenetics, Member of the German Center of Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
9
Department of Pediatrics, Division of Newborn Medicine, University of Southern California, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
10
Brain and Lung Epigenetics (BLUE), Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Université Paris-Est Créteil (UPEC), 94010 Créteil, France
11
Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Children’s Hospital Los Angeles and University of Southern California, Los Angeles, CA 90027, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2020, 9(4), 859; https://doi.org/10.3390/cells9040859
Received: 21 January 2020 / Revised: 5 March 2020 / Accepted: 13 March 2020 / Published: 2 April 2020
(This article belongs to the Special Issue FGF Signaling in Lung Development, Homeostasis and Disease)
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. View Full-Text
Keywords: miR-154; AT2; hyperoxia; Caveolin1; Tgf-ß1; alveolar simplification miR-154; AT2; hyperoxia; Caveolin1; Tgf-ß1; alveolar simplification
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MDPI and ACS Style

Chao, C.-M.; Carraro, G.; Rako, Z.A.; Kolck, J.; Sedighi, J.; Zimmermann, V.; Moiseenko, A.; Wilhelm, J.; Young, B.M.; Chong, L.; Wu, J.; Contreras, A.; Minoo, P.; Barreto, G.; Warburton, D.; Bellusci, S. 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. Cells 2020, 9, 859. https://doi.org/10.3390/cells9040859

AMA Style

Chao C-M, Carraro G, Rako ZA, Kolck J, Sedighi J, Zimmermann V, Moiseenko A, Wilhelm J, Young BM, Chong L, Wu J, Contreras A, Minoo P, Barreto G, Warburton D, Bellusci S. 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. Cells. 2020; 9(4):859. https://doi.org/10.3390/cells9040859

Chicago/Turabian Style

Chao, Cho-Ming, Gianni Carraro, Zvonimir A. Rako, Johannes Kolck, Jamschid Sedighi, Volker Zimmermann, Alena Moiseenko, Jochen Wilhelm, Brittany M. Young, Lei Chong, Jin Wu, Adriana Contreras, Parviz Minoo, Guillermo Barreto, David Warburton, and Saverio Bellusci. 2020. "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" Cells 9, no. 4: 859. https://doi.org/10.3390/cells9040859

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