LncRNA-NEAT1 from the competing endogenous RNA network promotes cardioprotective efficacy of mesenchymal stem cell-derived exosomes induced by macrophage migration inhibitory factor via the miR-142-3p/FOXO1 signaling pathway

Abstract

Abstract Aims Extracellular vesicles, especially exosomes, have emerged as key mediators of intercellular communication with the potential to improve cardiac function as part of cell-based therapies. We previously demonstrated that the cardioprotective factor, macrophage migration inhibitory factor (MIF), had an optimizing effect on mesenchymal stem cells (MSCs). The aim of this study was to determine the protective function of exosomes derived from MIF-pretreated MSCs in cardiomyocytes and to explore the underlying mechanisms. Methods and results Exosomes were isolated from control MSCs (exosome) and MIF-pretreated MSCs (exosomeMIF), and delivered to cardiomyocytes subjected to H2O2 in vitro. Regulatory long non-coding RNAs (lncRNAs) activated by MIF pretreatment were explored using genomics approaches. ExosomeMIF protected cardiomyocytes from H2O2-induced apoptosis. Mechanistically, we identified lncRNA-NEAT1 as a mediator of exosomeMIF by regulating the expression of miR-142-3p and activating Forkhead class O1 (FOXO1). The cardioprotective effects of exosomeMIF were consistently abrogated by depletion of lncRNA-NEAT1, by overexpression of miR-142-3p, or by FOXO1 silencing. Furthermore, exosomeMIF inhibited H2O2-induced apoptosis through modulating oxidative stress. Conclusions Exosomes obtained from MIF-pretreated MSCs have a protective effect on cardiomyocytes. The lncRNA-NEAT1 functions as an anti-apoptotic molecule via competitive endogenous RNA activity towards miR-142-3p. LncRNA-NEAT1/miR-142-3p/FOXO1 at least partially mediates the cardioprotective roles of exosomeMIF in protecting cardiomyocytes from apoptosis.