Reprogrammed lung epithelial cells by decrease of miR-451a in extracellular vesicles contribute to aggravation of...

Area of Science:

• Cell Biology
• Molecular Biology
• Pulmonary Medicine

Background:

• Extracellular vesicles (EVs) mediate intercellular communication in the human airways via microRNAs (miRNAs).
• The role of EV-derived miRNAs in maintaining pulmonary phenotypic homeostasis and their contribution to lung fibrogenesis remain incompletely understood.
• Epithelium-derived EVs are implicated in lung homeostasis, but their specific function in fibrotic disease requires elucidation.

Purpose of the Study:

• To investigate the functional role of miRNAs within epithelium-derived EVs in the context of lung fibrogenesis.
• To determine the impact of polyhexamethylene guanidine phosphate (PHMG-p) exposure on EV miRNA profiles and their downstream effects on lung tissue.
• To identify specific miRNA-target interactions involved in PHMG-p-induced pulmonary fibrosis.

Main Methods:

• Pulmonary fibrosis was induced in mice via PHMG-p instillation.
• EVs were isolated from conditioned media of untreated (EV-Con) and PHMG-p-treated BEAS-2B cells (EV-PHMG).
• Differential miRNA expression analysis in EVs, functional assays for epithelial-mesenchymal transition (EMT), and in vivo/in vitro therapeutic interventions were performed.

Main Results:

• PHMG-p exposure increased EV release from bronchial epithelial cells and altered miRNA content, notably downregulating miR-451a.
• miR-451a targets the transcription factor OSR1, which is implicated in fibrosis-associated gene regulation.
• Transfer of miR-451a via EVs suppressed OSR1, inhibited EMT, and alleviated fibrogenesis in PHMG-p-exposed lungs and cells.

Conclusions:

• Downregulation of EV miR-451a contributes to lung fibrogenesis by increasing OSR1 levels and promoting EMT.
• Restoring miR-451a levels in EVs demonstrates a potential therapeutic strategy for mitigating lung fibrosis.
• EV miR-451a plays a critical role in maintaining pulmonary homeostasis by regulating OSR1 and preventing fibrosis, offering a novel therapeutic target.