Intrapericardial long non-coding RNA– Tcf21 antisense RNA inducing demethylation administration promotes cardiac repair
Year: 2023
Type: article
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.
Source: European Heart Journal
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G3589610080, Drug Delivery and Biomimetic Approaches for Optimal Stem Cell Therapy, Surgical Microneedle Patch Delivery of CMMP for Heart Repair, Targeted Anti-IL-1β Platelet Mimetics for Cardiac Detoxification and Repair, Engineer Artificial Exosomes for Treating Myocardial Infarction, Enhancing vascular delivery of stem cells and microparticles, Cardiac Patches Loaded with Stem Cell Factors to Treat Heart Failure, Restoring exosome functions in post-MI hearts by modulating miR-21, Harnessing Platelet-Endothelial Interactions for Exosome Delivery, Developing Long Noncoding RNA Therapy for Precision Cardiac Repair
OpenAlex ID: W4324130286