Exosomes from MiR-30d-5p-ADSCs Reverse Acute Ischemic Stroke-Induced, Autophagy-Mediated Brain Injury by Promoting M2 Microglial/Macrophage Polarization

Abstract

Background/Aims: Recent studies have indicated that exosomes secreted from adipose-derived stem cells (ADSCs) have important effects in the treatment of ischemic injury. However, the treatment mechanism is unclear. This study aimed to investigate whether ADSC-derived exosomes enriched with microRNA (miR)-30d-5p have a protective effect on acute ischemic stroke (AIS). Methods: In the current study, inflammatory factors and miR-30d-5p expression were assessed in 70 subjects with AIS and 35 healthy controls. Exosomes were characterized by transmission electron microscopy and further examined using nanoparticle tracking analyses. A rat model of AIS and an in vitro model of oxygen- and glucose-deprived (OGD) primary microglia were established to study the protective mechanism of exosomes from miR-30d-5p-overexpressing ADSCs in ischemia-induced nerve injury. Results: The results showed that following AIS, the expression of inflammatory cytokines increased, while the anti-inflammatory cytokines IL-4, IL-10, and miR-30d-5p decreased both in patients and in animal models. Moreover, in vitro studies demonstrated that suppression of autophagy significantly reduced the OGD-induced inflammatory response. In addition, exosome treatment was more effective in suppressing the inflammatory response by reversing OGD-induced and autophagy-mediated microglial polarization to M1. Furthermore, in vivo studies showed that exosomes derived from ADSCs significantly decreased the cerebral injury area of infarction by suppressing autophagy and promoting M2 microglia/macrophage polarization. Conclusions: Our results suggest that miR-30d-5p-enhanced ADSC-derived exosomes prevent cerebral injury by inhibiting autophagy-mediated microglial polarization to M1.

Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells

“…Notable studies have reported that BM-MSC exosomes could repair spinal cord injury by suppressing the activation of A1 neurotoxic reactive astrocytes induced by activated microglia (86) or by inhibiting the complement system (105) and the NF-κB signaling pathway (46,57,105). Meanwhile, SC-EVs have been observed to polarize microglia from classic M1 to antiinflammatory M2 phenotypes (59,85,106,107), which might be attributed to the targeted suppression of the 3 ′ -UTR mRNA expression in Beclin-1 and Atg5 and inhibition of autophagymediated microglial polarization toward pro-inflammatory state by miR-30d-5p-expressing EVs (59) ( Table 1). Thus, SC-EVs create a microenvironment conducive to nerve cell repair by inducing expression of microglial immunotolerance phenotypes in NS diseases.…”

microRNA profiling in the Weddell seal suggests novel regulatory mechanisms contributing to diving adaptation

“…miR-499 is also important in ischemic postconditioning following cardiac challenge by ischemia-reperfusion [42]. miR-30d-5p oxerexpression limits ischemic injury and has demonstrated experimental ischemic protection in other tissues [43]. miR-490-3p is anti-atherosclerotic in human coronary artery smooth muscle cells [44].…”

Extracellular Vesicles: The New Frontier of Stem Cell Regenerative Medicine?

“…Generally, EVs can promote myocardial regeneration and restore cardiac function by directly activating cardiac precursor cells and inducing their differentiation, through the promotion of cardiomyocytes survival and proliferation. EVs are also able to inhibit cardiomyocytes apoptosis, to stimulate angiogenesis, and finally to regulate the inflammatory response in the damaged area [166][167][168][169]. One of the possible mechanism is related to the increase in cardiomyocytes of Bcl-2 expression, responsible for reduction of cardiac cell apoptosis, promotion of proliferation and angiogenesis [170].…”

“…Other miRNAs involved in myocardium protection are miRNA-21a-5p, miRNA -21, miRNA-125-5p and miRNA93-5p [174][175][176][177]. Besides, overexpression of miRNA-30d inhibited autophagy and promoted polarization of macrophages into the anti-inflammatory M2 type [169]. The expression of inflammatory factors was also down-regulated by the miRNA-126 [178].…”