Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19

Abstract

Aims Naturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal stem cells (MSCs) in a rat model of acute myocardial infarction (AMI). The aim of this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent cardioprotective function in a rat model of AMI and if so to explore the underlying mechanisms. Methods and results Exosomes were isolated from control MSCs (MSC-Exo) and ATV-pretreated MSCs (MSCATV-Exo) and were then delivered to endothelial cells and cardiomyocytes in vitro under hypoxia and serum deprivation (H/SD) condition or in vivo in an acutely infarcted Sprague-Dawley rat heart. Regulatory genes and pathways activated by ATV pretreatment were explored using genomics approaches and functional studies. In vitro, MSCATV-Exo accelerated migration, tube-like structure formation, and increased survival of endothelial cells but not cardiomyocytes, whereas the exosomes derived from MSCATV-Exo-treated endothelial cells prevented cardiomyocytes from H/SD-induced apoptosis. In a rat AMI model, MSCATV-Exo resulted in improved recovery in cardiac function, further reduction in infarct size and reduced cardiomyocyte apoptosis compared to MSC-Exo. In addition, MSCATV-Exo promoted angiogenesis and inhibited the elevation of IL-6 and TNF-α in the peri-infarct region. Mechanistically, we identified lncRNA H19 as a mediator of the role of MSCATV-Exo in regulating expression of miR-675 and activation of proangiogenic factor VEGF and intercellular adhesion molecule-1. Consistently, the cardioprotective effects of MSCATV-Exo was abrogated when lncRNA H19 was depleted in the ATV-pretreated MSCs and was mimicked by overexpression of lncRNA H19. Conclusion Exosomes obtained from ATV-pretreated MSCs have significantly enhanced therapeutic efficacy for treatment of AMI possibly through promoting endothelial cell function. LncRNA H19 mediates, at least partially, the cardioprotective roles of MSCATV-Exo in promoting angiogenesis.

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

“…Exosomes comprise functional miRNAs and lncRNAs and serve as intercellular shuttles delivering important messages to affect the gene expression and cellular functions of distant organs [42,43]. LncRNAs in exosomes were previously shown to be tissue-specific and stage-specific, but to also be modulated by the environment [44,45]. The current study showed that among the potential cardioprotective lncRNAs, lncRNA-NEAT1 was highly expressed in exosomes derived from MSCs treated with MIF.…”

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…Indeed, somatic MSCs have been stimulated either under hypoxic and/or pro-inflammatory conditions, resulting in the implementation of their secreted EVs to provide tissue repair, along with modulatory and pro-angiogenic effects [188,[193][194][195]. Pharmacological priming by atorvastatin, a well-established lipid-lowering drug that can enhance stromal progenitor cell cardioprotective effects, has also been reported [196]. Another well-accepted approach is to increase EV function via genetic overexpression of specific miRNAs within parental MSC as vesicle cargo loading strategy; as result, a significant fold enrichment of those regulatory miRNAs putatively involved in EV paracrine ability has been observed, thus enhancing their phenotypic effects on responder cells [189,190,197].…”

Exosomal LncRNA–NEAT1 derived from MIF-treated mesenchymal stem cells protected against doxorubicin-induced cardiac senescence through sponging miR-221-3p

“…A number of recent studies have revealed that lncRNAs play an important role in senescence-related cardiac injury [42]. Some lncRNAs contained in exosomes serve as important messages to alter gene expression and cellular functions of distant organs, usually acting as regulators in many cardiac pathological processes [14]. Modifying a cell culture environment, leading to changes in components of lncRNAs, and investigating the molecular and biological functions of lncRNAs are important in providing new insights into the treatment of Dox-induced cardiac injury.…”

“…There is mounting evidence that MSCs related repairment or regeneration of damaged cardiac tissues, primarily by means of exosomes release, which are safer and more effective [13]. At meanwhile, the contribution of exosomes to could be further improved though modifying MSCs [14]. When developing exosome-based therapeutics, exosomes were found to elicit differential effects on recipient cells depending on the cultural environment of parent cells [15].…”