Regulation of alveolar septation by microRNA-489

Abstract

MicroRNAs (miRs) are small conserved RNA that regulate gene expression. Bioinformatic analysis of miRNA profiles during mouse lung development indicated a role for multiple miRNA, including miRNA-489. miR-489 increased on completion of alveolar septation [postnatal day 42 (P42)], associated with decreases in its conserved target genes insulin-like growth factor-1 (Igf1) and tenascin C (Tnc). We hypothesized that dysregulation of miR-489 and its target genes Igf1 and Tnc contribute to hyperoxia-induced abnormal lung development. C57BL/6 mice were exposed to normoxia (21%) or hyperoxia (85% O2) from P4 to P14, in combination with intranasal locked nucleic acid against miR-489 to inhibit miR-489, cytomegalovirus promoter (pCMV)-miR-489 to overexpress miR-489, or empty vector. Hyperoxia reduced miR-489 and increased Igf1 and Tnc. Locked nucleic acid against miR-489 improved lung development during hyperoxia and did not alter it during normoxia, whereas miR-489 overexpression inhibited lung development during normoxia. The 3' untranslated region in vitro reporter studies confirmed Igf1 and Tnc as targets of miR-489. While miR-489 was of epithelial origin and present in exosomes, its targets Igf1 and Tnc were produced by fibroblasts. Infants with bronchopulmonary dysplasia (BPD) had reduced lung miR-489 and increased Igf1 and Tnc compared with normal preterm or term infants. These results suggest increased miR-489 is an inhibitor of alveolar septation. During hyperoxia or BPD, reduced miR-489 and increased Igf1 and Tnc may be inadequate attempts at compensation. Further inhibition of miR-489 may permit alveolar septation to proceed. The use of specific miRNA antagonists or agonists may be a therapeutic strategy for inhibited alveolarization, such as in BPD.

Loss of CD73-mediated extracellular adenosine production exacerbates inflammation and abnormal alveolar development in newborn mice exposed to prolonged hyperoxia

“…We did find a significant increase in IGF-1 in CD73 −/− mice in hyperoxia. Elevations in IGF-1 are associated with abnormal lung development in animal models of BPD (38) and human BPD lung samples (26,39). Taken together, the increase in IGF-1 in hyperoxia could explain the abnormal pulmonary development in CD73 −/− mice.…”

Exosomal microRNA predicts and protects against severe bronchopulmonary dysplasia in extremely premature infants

“…Exosomal lipid bilayers pack the exosomal miRNAs within, and protect them from, enzymatic degradation, resulting in a long and stable duration of expression suitable for a biomarker (13,14). Recent studies have shown that miRNAs have central roles in multiple aspects of lung inflammation and disease pathogenesis (12,(15)(16)(17). Hence, we hypothesized that the airway exosomal miRNA signature at birth would predict the future development of severe BPD.…”

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

“…lung development, which is relevant to BPD, several microRNA candidates have been proposed as pathogenic players, including miR-150(Narasaraju et al, 2015), miR-489(Olave et al, 2016), miR-29b(Durrani-Kolarik et al, 2017), the miR-19/72 cluster(Rogers et al, 2015;Robbins et al, 2016), and epithelial miR-34a(Syed et al, 2017), but transgenic mouse studies have only validated a causal role for epithelial miR-34a (most likely by targeting angiopoietin) in arrested alveolarization, where miR-34a levels were also documented to be elevated in the lungs of BPD patients(Syed et al, 2017). Ours is the first report of a causal role being validated for any microRNA/mRNA target interaction in aberrant lung alveolarization, as well as the first-in-mouse use of a TSB in vivo in an animal…”