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)alpha-expressing myofibroblasts, a cell type critical for proper lung alveolarization. Global deletion of miR-34a; and inducible, conditional deletion of miR-34a in PDGFRalpha(+) 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 PDGFRalpha(+) 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.
- Ruiz-Camp, J.
- Quantius, J.
- Lignelli, E.
- Arndt, P. F.
- Palumbo, F.
- Nardiello, C.
- Surate Solaligue, D. E.
- Sakkas, E.
- Mizikova, I.
- Rodriguez-Castillo, J. A.
- Vadasz, I.
- Richardson, W. D.
- Ahlbrecht, K.
- Herold, S.
- Seeger, W.
- Morty, R. E.
Keywords
- *bronchopulmonary dysplasia
- *hyperoxia
- *lung development
- *miR-34a
- *platelet-derived growth factor
