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EMBO Mol Med. 2019 Mar;11(3). pii: e9448. doi: 10.15252/emmm.201809448.

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

Author information

1
Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
2
Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
3
Wolfson Institute for Biomedical Research, University College London, London, UK.
4
Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany rory.morty@mpi-bn.mpg.de.

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.

KEYWORDS:

bronchopulmonary dysplasia; hyperoxia; lung development; miR‐34a; platelet‐derived growth factor

PMID:
30770339
DOI:
10.15252/emmm.201809448
Free PMC Article

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