Human umbilical cord mesenchymal stem cell-derived exosomal miR-146a-5p reduces microglial-mediated neuroinflammation via suppression of the IRAK1/TRAF6 signaling pathway after ischemic stroke

Abstract

To investigate the therapeutic mechanism of action of transplanted stem cells and develop exosome-based nanotherapeutics for ischemic stroke, we assessed the effect of exosomes (Exos) produced by human umbilical cord mesenchymal stem cells (hUMSCs) on microglia-mediated neuroinflammation after ischemic stroke. Our results found that injected hUMSC-Exos were able to access the site of ischemic damage and could be internalized by cells both in vivo and in vitro . In vitro , treatment with hUMSC-Exos attenuated microglia-mediated inflammation after oxygen-glucose deprivation (OGD). In vivo results demonstrated that treatment with hUMSC-Exos significantly reduced infarct volume, attenuated behavioral deficits, and ameliorated microglia activation, as measured three days post-transient brain ischemia. Furthermore, miR-146a-5p knockdown (miR-146a-5p k/d Exos) partially reversed the neuroprotective effect of hUMSC-Exos. Our mechanistic study demonstrated that miR-146a-5p in hUMSC-Exos reduces microglial-mediated neuroinflammatory response through IRAK1/TRAF6 pathway. We conclude that miR-146a-5p derived from hUMSC-Exos can attenuate microglia-mediated neuroinflammation and consequent neural deficits following ischemic stroke. These results elucidate a potential therapeutic mechanism of action of mesenchymal stem cells and provide evidence that hUMSC-Exos represent a potential cell-free therapeutic option for ischemic stroke.

Exosomes Derived from miR-146a-5p-Enriched Mesenchymal Stem Cells Protect the Cardiomyocytes and Myocardial Tissues in the Polymicrobial Sepsis through Regulating MYBL1

“…MiR-146a-5p, belongs to the member of miR-146a family, has multiple biological functions including anticancer, antiinflammatory, and antioxidative [44,45]. In cardiovascular disease, miR-146a-5p in MSC-derived exosomes could reduce the neuroinflammatory response in ischemic stroke and alleviate the intracerebral hemorrhage (ICH) [29,30]. In this study, through bioinformatics analysis, we found that miR-146a-5p served as the main gene to regulate the inhibitory effect of MSCs-Exo on sepsis.…”

“…Meanwhile, miR-146a-5p in MSCs-Exo exerts important role in cardiovascular disease. For instance, miR-146a-5p in hUMSCs-Exo reduced microglial-mediated neuroinflammatory response via inhibiting the IRKA1/TRAF6 signaling pathway in ischemic stroke [29]. MiR-146a-5p in BMSCderived exosome could alleviate the intracerebral hemorrhage (ICH) through repressing neuronal apoptosis and microglial M1 polarization [30].…”

Potential Role of Exosomes in Ischemic Stroke Treatment

“…microRNA-34c in astrocyte-released exosomes exerted a neuroprotective effect by downregulating TLR7 and NF-κB/MAPK pathways [ 107 ]. miR-146a-5p derived from human umbilical MSC exosomes inhibited microglial-mediated neuroinflammation via the IRAK1/TRAF6 pathway [ 108 ]. Accordingly, anti-inflammation is a pivotal mechanism against ischemic injury; targeting specific exosomes related to it may be beneficial.…”

Exosomes in Age-Related Cognitive Decline: Mechanistic Insights and Improving Outcomes

“…Interestingly, such beneficial effects on cognition and neuroinflammation were comparable when exosomes were specifically targeted to the brain or administered systemically, highlighting the capacity of these EVs to exert their effects across the BBB ( Cui et al, 2018 , 2019 ). Follow-up studies have expounded on these findings by illustrating the exosomal moderation of neuroinflammatory processes and ensuing benefits to cognitive performance may be attributed to effects on microglia specifically (i.e., the resident macrophage of the CNS) ( Ding et al, 2018 ; Li et al, 2020 ; Zhang et al, 2021 ).…”