Human bronchial epithelial cell‐derived extracellular vesicle therapy for pulmonary fibrosis via inhibition of TGF‐β‐WNT crosstalk

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)‐β and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signalling, human bronchial epithelial cell‐derived EVs (HBEC EVs) inhibit TGF‐β mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell‐derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non‐canonical WNT signalling pathways. Among enriched miRNA species present in HBEC EVs, miR‐16, miR‐26a, miR‐26b, miR‐141, miR‐148a, and miR‐200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin‐induced lung fibrosis development accompanied by reduced expression of both β‐catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti‐fibrotic properties. They further suggest that, via miRNA‐mediated inhibition of TGF‐β‐WNT crosstalk, HBEC EVs administration can be a promising anti‐fibrotic modality of treatment for IPF.

Exosomes of A549 Cells Induced Migration, Invasion, and EMT of BEAS-2B Cells Related to let-7c-5p and miR-181b-5p

“…Numerous current research have proved that exosomes secreted by donor cells can transmit bioactive substance to neighboring cells to influence their characteristic and reprogram the phenotypes of recipient cells, with the potential to modulate carcinogenic consequences ( 54 , 55 ). Exosomes derived from HQ-transformed malignant cells were proven to be able to transmit miR-221 to normal recipient cells to promote cell viability ( 56 ).…”

Endothelial Microparticles Derived from Primary Pulmonary Microvascular Endothelial Cells Mediate Lung Inflammation in Chronic Obstructive Pulmonary Disease by Transferring microRNA-126

“…Recently, there have been novel findings to prove that EVs derived from non-mesenchymal stem cells also had therapeutic effects. In 2021, Kadota et al 47 confirmed that extracellular vesicles derived from normal human bronchial epithelium can inhibit TGF-β/Wnt pathway improves pulmonary fibrosis both in vitro and in vivo. Interestingly, a study previously published by Kadota and his team showed that extracellular vesicles derived from human bronchial epithelial cells stimulated by cigarette smoke can significantly promote the differentiation of pulmonary myofibroblasts through autophagy, and finally participate in the pathogenesis of COPD.…”

The therapeutic capacity of bone marrow MSC‐derived extracellular vesicles in Achilles tendon healing is passage‐dependent and indicated by specific glycans

“…Nanoparticle tracking analysis was performed to determine the size distribution and the particle number using the NanoSight system (NanoSight Ltd., Salisbury, UK) and nanoparticle tracking software as previously described [20].…”