Targeting miR-34a/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 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 PDGFRαcells afforded partial protection to the developing lung against hyperoxia-induced perturbations to lung architecture.mRNA was identified as the relevant miR-34a target, and using a target site blocker, the miR-34a/interaction was validated as a causal actor in arrested lung development. An antimiR directed against miR-34a partially restored PDGFRαmyofibroblast 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/interaction to manage arrested lung development associated with preterm birth.