Intrapericardial long non-coding RNA–Tcf21 antisense RNA inducing demethylation administration promotes cardiac repair

医学 心肌梗塞 纤维化 肌成纤维细胞 心功能曲线 心脏纤维化 间充质干细胞 微泡 体内 核糖核酸 细胞生物学 长非编码RNA 心脏病学 胞外囊泡 癌症研究 内科学 心力衰竭 病理 生物 小RNA 基因 生物化学 生物技术
作者
Dashuai Zhu,Shuo Liu,Ke Huang,Junlang Li,Xuan Mei,Zhenhua Li,Ke Cheng
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:44 (19): 1748-1760 被引量:28
标识
DOI:10.1093/eurheartj/ehad114
摘要

Abstract Aims Epicardium and epicardium-derived cells are critical players in myocardial fibrosis. Mesenchymal stem cell–derived extracellular vesicles (EVs) have been studied for cardiac repair to improve cardiac remodelling, but the actual mechanisms remain elusive. The aim of this study is to investigate the mechanisms of EV therapy for improving cardiac remodelling and develop a promising treatment addressing myocardial fibrosis. Methods and results Extracellular vesicles were intrapericardially injected for mice myocardial infarction treatment. RNA-seq, in vitro gain- and loss-of-function experiments, and in vivo studies were performed to identify targets that can be used for myocardial fibrosis treatment. Afterward, a lipid nanoparticle–based long non-coding RNA (lncRNA) therapy was prepared for mouse and porcine models of myocardial infarction treatment. Intrapericardial injection of EVs improved adverse myocardial remodelling in mouse models of myocardial infarction. Mechanistically, Tcf21 was identified as a potential target to improve cardiac remodelling. Loss of Tcf21 function in epicardium-derived cells caused increased myofibroblast differentiation, whereas forced Tcf21 overexpression suppressed transforming growth factor-β signalling and myofibroblast differentiation. LncRNA–Tcf21 antisense RNA inducing demethylation (TARID) that enriched in EVs was identified to up-regulate Tcf21 expression. Formulated lncRNA–TARID-laden lipid nanoparticles up-regulated Tcf21 expression in epicardium-derived cells and improved cardiac function and histology in mouse and porcine models of myocardial infarction. Conclusion This study identified Tcf21 as a critical target for improving cardiac fibrosis. Up-regulating Tcf21 by using lncRNA–TARID-laden lipid nanoparticles could be a promising way to treat myocardial fibrosis. This study established novel mechanisms underlying EV therapy for improving adverse remodelling and proposed a lncRNA therapy for cardiac fibrosis.
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