Idiopathic pulmonary fibrosis airway basal progenitor cells-derived extracellular vesicles mediate fibroblast activation to promote progression

Idiopathic pulmonary fibrosis (IPF) is a rare, progressive fibrotic disease primarily characterized by recurrent epithelial injury and fibroblast activation. Recent studies have indicated that the accumulation of abnormal airway basal progenitor cells (ABCs) may significantly contribute to the promotion of fibrosis, serving as a prerequisite for the onset and progression of IPF. However, the underlying mechanisms remain inadequately understood. ABCs form IPF patients and healthy controls were obtained by bronchoscopic brushing and cultured with specific medium. Collecting the cell supernatant, their EVs were isolated by ultracentrifuge. Human lung fibroblasts were treated with EVs to evaluate the effect of activation, proliferation, and migration in vitro. Furthermore, the administration of EVs via inhalation to healthy mice and pulmonary fibrosis model mice was undertaken in order to ascertain the impact on fibrosis progression in vivo. Furthermore, a comprehensive profiling of the microRNA presented within EVs from IPF- and health control-ABCs was conducted. IPF and health ABCs were extracted and identified successfully, with IPF ABCs revealed to promote fibroblast activation. Subsequently, the EVs from IPF and healthy ABCs were isolated and characterized. Our findings indicated that IPF EVs exhibited a predominant role in fibroblast activation, but didn’t contribute to proliferation and migration. However, control-EVs were found to promote fibroblasts proliferation and migration in vitro. Furthermore, we found IPF-EVs induced pulmonary septal thickening and collagen deposition in vivo, while health-EVs suppressed collagen deposition in lung fibrosis induced by bleomycin. Furthermore, the presence of differentially expressed microRNAs in EVs derived from IPF and health ABCs (including has-miR-141-3p, hsa-let-7b-3p, has-let-7f-1-3p, etc.) has been observed. These differentially expressed miRNAs have the potential to enrich in collagen metabolic procession, WNT signaling, and JAK/STAT signaling pathway. These findings suggest that EVs derived from ABCs are associated with fibroblast-related fibrotic responses and may contribute to intercellular communication during IPF progression.