Targeting miR‐34a/ Pdgfra 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 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.

miRNAs in Lung Development and Diseases

“…We observed a dual function of miR-34a, specifically in the late stage of lung development and pathogenesis of IPF. In newborn mice, miR-34a impaired alveolarization, and in adult mice, the miRNA alleviated the progression of pulmonary fibrosis [24,81]. Figure 3 illustrates the functions of miR-34a in the mouse lung.…”

“…Furthermore, overexpression of miR-127 in fetal rat lung (E14) culture increased terminal and internal bud sizes.Regarding alveolarization, several studies have been done in bronchopulmonary dysplasia (BPD) mouse models. For example, hyperoxia-induced impairment in alveolarization was partially mitigated in miR-34a −/− mice [24]. In another study, the administration of miR-29b, nonetheless, improved alveolarization and attenuated fibrotic signaling in postnatal day 28 mice (exposed to…”

The involvement of HDAC3-mediated inhibition of microRNA cluster 17-92 in hyperoxia-mediated impairment of lung development in neonatal rats

“…Previous literature has reported that HDAC3 was participated in the remodeling and expansion of distant alveolar vesicles into primitive pulmonary alveolus by regulating the miR-17-92 cluster [14], which commonly constitutes to the occurrence of BPD in premature infants [15]. Based on the aforementioned evidence, it was suggested that HDAC3 may be involved in the progression of BPD.…”

“…The cell pellet was then resuspended in preheated (37°C) high-glucose Dulbecco's modified Eagle's medium (DMEM) containing 10% (v/v) fetal bovine serum (FBS), 100 U/mL penicillin (ThermoFisher Scientific, Waltham, MA, USA) and 100 μg/mL streptomycin (ThermoFisher Scientific), followed by inoculation into a T-75 cell culture flask (1 flask per lung), then by passage in low-glucose DMEM containing 10% (v/v) FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin. The cells used in this study were primary isolated and cultured lung fibroblasts [15].…”

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

“…4h; Supplementary Figure 4e). Saa3 has been shown to be upregulated in a lamb preterm lung injury model 18 and to regulate Pdgfra 19 , which has a well established role in lung development in animal models [20][21][22] . Decreased PDGFRA expression was associated with increased risk for male patients to develop BPD 23 .…”