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

Ruiz-Camp J, Quantius J, Lignelli E, Arndt PF, Palumbo F, Nardiello C, Surate Solaligue DE, Sakkas E, Mižíková I, Rodríguez-Castillo JA, Vadász I, Richardson WD, Ahlbrecht K, Herold S, Seeger W, Morty RE

EMBO Mol Med 11 (3) - [2019-03-00; online 2019-02-17]

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.

PubMed 30770339

DOI 10.15252/emmm.201809448

Crossref 10.15252/emmm.201809448

pmc: PMC6404112
pii: emmm.201809448