Ischemic Preconditioning Potentiates the Protective Effect of Stem Cells through Secretion of Exosomes by Targeting Mecp2 via miR-22

Abstract

Mesenchymal stem cells (MSCs) have potential application for the treatment of ischemic heart diseases. Besides differentiation properties, MSCs protect ischemic cardiomyocytes by secretion of paracrine factors. In this study, we found exosomes enriched with miR-22 were secreted by MSCs following ischemic preconditioning (ExoIPC) and mobilized to cardiomyocytes where they reduced their apoptosis due to ischemia. Interestingly, by time-lapse imaging, we for the first time captured the dynamic shedding of miR-22 loaded exosomes from cytosol to extracellular space. Furthermore, the anti-apoptotic effect of miR-22 was mediated by direct targeting of methyl CpG binding protein 2 (Mecp2). In vivo data showed that delivery of ExoIPC significantly reduced cardiac fibrosis. Our data identified a significant benefit of ExoIPC for the treatment of cardiac diseases by targeting Mecp2 via miR-22.

Engineered Exosomes With Ischemic Myocardium‐Targeting Peptide for Targeted Therapy in Myocardial Infarction

“…Through a comparison of cardiac‐resident progenitor cell–secreted exosomes and BMSC‐secreted exosomes, Barile et al30 explained that the cardioprotection of exosomes may act via the pregnancy‐associated plasma protein‐A mediated insulin‐like growth factor‐1 release and subsequently modulate intracellular protein kinase B and extracellular signal regulated kinase 1/2 phosphorylation. Feng et al31 demonstrated that exosomes released from ischemic preconditioned MSCs contained an increased amount of miR‐22, which could exert a silence effect on methyl CpG binding protein 2 to ameliorate apoptosis in mice with AMI. Our group also proved that MSC‐derived exosomes could inhibit inflammation, augment vasculogenesis, and restore cardiac function in MI by activating and modifying the microRNA profiles of cardiac stem cells 32, 33.…”

En el Infarto agudo al miocardio los niveles plasmáticos de microvesículas extracelulares se elevan más precozmente que el aumento de la Troponina-I

“…Otros métodos se basan en el uso de matriz de polímeros que permiten su fácil y rápida obtención. Este método, por lo demás, es aplicable en clínica debido a su bajo costo, al reducido tiempo de realización y no requiere personal especializado 8,[15][16][17][18][19] . En nuestro laboratorio, hemos implementado la extracción de MVECs mediante el uso de ExoQuick®, el cual purifica una fracción enriquecida de exosomas, que además se recomienda para la caracterización de diversas moléculas como proteínas y RNA 10,16-18, 20, 21 .…”

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

“…When MSCs were in vitro exposed to brain tissue extracted from rats subjected to middle cerebral artery occlusion, the miR-133b levels in the released exosomes from MSCs were significantly increased [229]. Thus, there is a feedback between the MSC and its environment, and through which ischemic conditions will modify the exosome contents, and consequently, the secreted exosomes affect and modify the tissue environment [205,230]. Regarding the brain, impacts of MSC-EV treatment were mainly studied in models for ischemic stroke and TBI and reduced apoptosis rates in affected brains, while promoted angiogenesis and neurogenesis [175-177, 215, 231-236].…”