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

Wnt信号通路 肌成纤维细胞 特发性肺纤维化 癌症研究 肺纤维化 串扰 细胞生物学 生物 衰老 基因沉默 纤维化 小RNA 医学 信号转导 病理 基因 内科学 光学 物理 生物化学
作者
Tsukasa Kadota,Yu Fujita,Jun Araya,Naoaki Watanabe,Shota Fujimoto,Hironori Kawamoto,Shunsuke Minagawa,Hiromichi Hara,Takashi Ohtsuka,Yusuke Yamamoto,Kazuyoshi Kuwano,Takahiro Ochiya
出处
期刊:Journal of extracellular vesicles [Wiley]
卷期号:10 (10) 被引量:116
标识
DOI:10.1002/jev2.12124
摘要

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.
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