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.
Highlights
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
Independent validation by real-time RT–PCR revealed that miR-34a-5p levels were increased at P3, P5, and P14 in hyperoxia-exposed lungs (Fig 1B), with little or no impact on miR-34b-5p or miR-34c-5p (Fig 1B), or miR-34a-3p, miR-34b-3p, or miR-34c-3p (Fig 1C) levels noted
Ablation of miR-34a expression in PDGFRa+ cells did not impact hyperoxia-provoked perturbations to septal thickness (Fig 3K), which we attribute to the tamoxifen solvent, Miglyol, a complex fatty acid-derivative mixture, which we propose limited the impact of hyperoxia on septal thickening analogous to that reported for chemically related cottonseed oil (Nardiello et al, 2017b), since Miglyol alone is known to attenuate normal lung development (Fehl et al, 2019)
Summary
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 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. Bronchopulmonary dysplasia (BPD), a serious complication of preterm birth (Jobe, 2016), is characterized by arrested alveolarization of lungs of infants, arising from oxygen toxicity and mechanical injury during oxygen supplementation to manage respiratory failure How these insults impair lung alveolarization is unclear (Surate Solaligue et al, 2017; Morty, 2018). EMBO Molecular Medicine miR-34a/Pdgfra interactions in BPD Jordi Ruiz-Camp et al interaction is disease relevant, and can be therapeutically targeted to partially restore lung alveolarization under pathological conditions These data highlight a new mediator, and druggable target, in arrested alveolarization associated with preterm birth
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