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.

Autor: Chao CM; 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.; 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.; Division of General Pediatrics and Neonatology, University Children's Hospital Gießen, Justus-Liebig-University, 35392 Giessen, Germany., Carraro G; Cedars-Sinai Medical Center, Lung and Regenerative Medicine Institutes, Department of Medicine, Los Angeles, CA, 90027, USA., Rako ZA; 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., Kolck J; 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., Sedighi J; 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., Zimmermann V; 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., Moiseenko A; 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., Wilhelm J; 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., Young BM; Department of Neurology, University of California, Los Angeles, CA 90095, USA., Chong L; Institute of Pediatrics, Discipline of Pediatric Respiratory Medicine, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, China., Wu J; College of Life and Environmental Sciences, Wenzhou University, Wenzhou 325027, Zhejiang, China., Contreras A; 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., Minoo P; Department of Pediatrics, Division of Newborn Medicine, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA., Barreto G; 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.; Brain and Lung Epigenetics (BLUE), Glycobiology, Cell Growth and Tissue Repair Research Unit (Gly-CRRET), Université Paris-Est Créteil (UPEC), 94010 Créteil, France., Warburton D; 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., Bellusci S; 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.; 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.
Jazyk: angličtina
Zdroj: Cells [Cells] 2020 Apr 02; Vol. 9 (4). Date of Electronic Publication: 2020 Apr 02.
DOI: 10.3390/cells9040859
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje