Intrapericardial administration of lncRNA-TARID-laden lipid nanoparticles up-regulated Tcf21 expression and improved cardiac function and histology in mouse and porcine models of myocardial infarction.
Does intrapericardial administration of lncRNA-TARID-laden lipid nanoparticles improve cardiac remodelling and fibrosis in animal models of myocardial infarction?
Intrapericardial delivery of lncRNA-TARID via lipid nanoparticles up-regulates Tcf21 and improves cardiac remodelling and fibrosis in preclinical models of myocardial infarction.
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.
Zhu et al. (Mon,) conducted a other in Myocardial infarction. lncRNA-TARID-laden lipid nanoparticles and Extracellular vesicles was evaluated on Cardiac remodelling, cardiac function, and histology. Intrapericardial administration of lncRNA-TARID-laden lipid nanoparticles up-regulated Tcf21 expression and improved cardiac function and histology in mouse and porcine models of myocardial infarction.