Extracellular Vesicles from Fibroblasts Induce Epithelial-Cell Senescence in Pulmonary Fibrosis
Extracellular Vesicles from Fibroblasts Induce Epithelial-Cell Senescence in Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2020-0002oc
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发表时间：
2020-11-01
影响因子：
6.4
通讯作者：
Ochiya, Takahiro
中科院分区：
文献类型：
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作者：
Kadota, Tsukasa;Yoshioka, Yusuke;Ochiya, Takahiro
异常的上皮-间质相互作用在调节纤维化发展中具有关键作用。特发性肺纤维化（IPF）的发病机制中细胞外囊泡（EV）（包括外来体）的参与仍有待阐明。在这里，我们发现来自IPF患者的肺成纤维细胞（LF）通过EV介导的病原性货物转移到肺上皮细胞来诱导细胞衰老。从机制上讲，IPF LF衍生的EV增加了线粒体活性氧和相关线粒体！肺上皮细胞的损伤，导致DNA损伤反应的激活和随后的上皮细胞衰老。我们发现IPF LF衍生的EV含有升高水平的microRNA-23 b-3 p（miR-23 b-3 p）和miR-494- 3 p，其抑制SIRT 3，导致上皮EV诱导的表型变化。此外，在IPF LF衍生EV中发现的miR-23 b-3 p和miR-494- 3 p水平与IPF疾病严重程度呈正相关。这些发现表明，在IPF发病过程中观察到的加速上皮细胞线粒体损伤和衰老是由IPF成纤维细胞通过含microRNA的EV的新型旁分泌效应引起的。
Aberrant epithelial-mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increased mitochondrial reactive oxygen species and associated mitochondria! damage in lung epithelial cells, leading to activation of the DNA damage response and subsequent epithelial-cell senescence. We showed that IPF LF-derived EVs contain elevated levels of microRNA-23b-3p (miR-23b-3p) and miR-494-3p, which suppress SIRT3, resulting in the epithelial EV-induced phenotypic changes. Furthermore, the levels of miR-23b-3p and miR-494-3p found in IPF LF-derived EVs correlated positively with IPF disease severity. These findings reveal that the accelerated epithelial-cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel paracrine effect of IPF fibroblasts via microRNA-containing EVs.