Targeting miR‐34a/Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

• Published in: EMBO molecular medicine Vol. 11; no. 3; pp. 1 - n/a
• Main Authors: Ruiz‐Camp, Jordi, Quantius, Jennifer, Lignelli, Ettore, Arndt, Philipp F, Palumbo, Francesco, Nardiello, Claudio, Surate Solaligue, David E, Sakkas, Elpidoforos, Mižíková, Ivana, Rodríguez‐Castillo, José Alberto, Vadász, István, Richardson, William D, Ahlbrecht, Katrin, Herold, Susanne, Seeger, Werner, Morty, Rory E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2019; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Animals; Birth; bronchopulmonary dysplasia; Bronchopulmonary Dysplasia - metabolism; Clonal deletion; Disease Models, Animal; Dysplasia; EMBO35; Flow Cytometry; Fluorescent Antibody Technique; Gas exchange; Hyperoxia; Hyperoxia - metabolism; lung development; Lung diseases; Lungs; Mice; Mice, Inbred C57BL; MicroRNAs - metabolism; miRNA; miR‐34a; mRNA; Oxygen; platelet‐derived growth factor; Premature birth; Pulmonary Alveoli - metabolism; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Research Article; Toxicity; platelet‐derived growth factor; hyperoxia; bronchopulmonary dysplasia; miR‐34a; lung development
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201809448

Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth characterized by arrested lung alveolarization, which generates lungs that are incompetent for effective gas exchange. We report here deregulated expression of miR‐34a in a hyperoxia‐based mouse model of BPD, where miR‐34a expression was markedly increased in platelet‐derived growth factor receptor (PDGFR)α‐expressing myofibroblasts, a cell type critical for proper lung alveolarization. Global deletion of miR‐34a; and inducible, conditional deletion of miR‐34a in PDGFRα
+
cells afforded partial protection to the developing lung against hyperoxia‐induced perturbations to lung architecture.
Pdgfra
mRNA was identified as the relevant miR‐34a target, and using a target site blocker
in vivo
, the miR‐34a/
Pdgfra
interaction was validated as a causal actor in arrested lung development. An antimiR directed against miR‐34a partially restored PDGFRα
+
myofibroblast abundance and improved lung alveolarization in newborn mice in an experimental BPD model. We present here the first identification of a pathology‐relevant microRNA/mRNA target interaction in aberrant lung alveolarization and highlight the translational potential of targeting the miR‐34a/
Pdgfra
interaction to manage arrested lung development associated with preterm birth.
Synopsis
The pathogenic mechanisms underlying stunted lung development associated with bronchopulmonary dysplasia (BPD) are unknown. In this study, the interaction between miR 34a and the Pdgfra 3′‐UTR was validated as both a causal factor and a potentially “druggable” target in BPD driven by oxygen toxicity.
miR‐34a expression was increased by elevated oxygen levels in PDGFRα+ cells.
PDGFRα expression was negatively regulated by miR‐34a
in vitro
and
in vivo
.
Lung development was protected by genetic ablation of miR‐34a expression in PDGFRα+ cells
in vivo
.
PDGFRα+ cell abundance was partially restored by neutralization of miR‐34a using LNA antimiRs in developing lungs.
Disrupting the miR‐34a/Pdgfra mRNA interaction revealed a new pathogenic pathway that could be pharmacologically manipulated.
Graphical Abstract
The pathogenic mechanisms underlying stunted lung development associated with bronchopulmonary dysplasia (BPD) are unknown. In this study, the interaction between miR 34a and the Pdgfra 3′‐UTR was validated as both a causal factor and a potentially “druggable” target in BPD driven by oxygen toxicity.