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

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

Abstract 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 m...

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Main Authors: Jordi Ruiz‐Camp, Jennifer Quantius, Ettore Lignelli, Philipp F Arndt, Francesco Palumbo, Claudio Nardiello, David E Surate Solaligue, Elpidoforos Sakkas, Ivana Mižíková, José Alberto Rodríguez‐Castillo, István Vadász, William D Richardson, Katrin Ahlbrecht, Susanne Herold, Werner Seeger, Rory E Morty
Format: Article
Language:English
Published: Springer Nature 2019-02-01
Series:EMBO Molecular Medicine
Subjects:
bronchopulmonary dysplasia
hyperoxia
lung development
miR‐34a
platelet‐derived growth factor
Online Access:https://doi.org/10.15252/emmm.201809448
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Summary:Abstract 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.
ISSN:1757-4676
1757-4684

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