Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm newborns characterized by a simplification of the distal lung structure because of a lack of alveoli formation. The receptor platelet-derived growth factor receptor (PDGFR)alpha, expressed by alpha smooth muscle actin (SMA)+ myofibroblasts, is critical for a proper epithelial-mesenchymal cross-talk required for the formation of alveoli during secondary septation. In BPD, PDGFRalpha is found down regulated but the reason for this is unknown. In a study of mouse lungs exposed to a hyperoxia-based BPD animal model, a microRNA (miR) microarray revealed the up-regulation of miR 34a expression levels. Therefore, the aim was to reduce miR-34a levels in vivo and, for this, an experiment based on a global miR-34a deletion was carried out, resulting in an improvement of the alveolarization and decrease of the septal wall thickness in mice under hyperoxic conditions. As Pdgfra mRNA was found to be a miR-34a target, another experiment blocking the miR 34a Pdgfra interaction by means of TSBs was performed and resulted in an increased total number of alveoli and decreased mean septal wall thickness in mouse lungs under hyperoxic conditions. The same improved lung structure was observed when either miR-34a was deleted specifically in PDGFRalpha+ cells or blocked by an antagomiR-34a (AntmiR34a) in mice under hyperoxic conditions. Regarding the mechanism, miR 34a was expressed in cells located in the developing septa and showed a surprising up regulated miR-34a expression level in PDGFRalpha+ sorted cells from P5.5 newborn mice under hyperoxic conditions. The receptor PDGFRalpha is important for the transdifferentiation of myofibroblasts which are placed in the growing septal tips and producing extracellular matrix (ECM) compounds such as elastin under normal conditions. After blocking miR-34a by AntmiR34a, both PDGFRalpha+ cells and double-positive PDGFRalpha+/alphaSMA+ cells were partially rescued in the BPD animal model assessed by FACS. Additionally, a higher number of alphaSMA+ was observed in the septa together with a better deposition and distribution of elastin revealing a better myofibroblast function. In addition, AntmiR34a administration decreased the level of generalized apoptosis and contributed to a better cell organization in the septa. These data suggested a novel role of miR-34a as a new negative regulator of alveologenesis through Pdgfra in a BPD animal model.
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