Exosome-Shuttled circSHOC2 from IPASs Regulates Neuronal Autophagy and Ameliorates Ischemic Brain Injury via the miR-7670-3p/SIRT1 Axis

Abstract

The aim of the present study was to investigate the neuroprotective roles and mechanisms of the circular RNA circSHOC2 in ischemic-preconditioned astrocyte-derived exosomes (IPAS-EXOs) against ischemic stroke. We established an ischemia model based on oxygen glucose deprivation (OGD) in vitro and isolated resultant exosomes from astrocytes. Neuronal viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assays and TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining, respectively. Autophagy-related proteins were analyzed by western blotting. We found that exosomes derived from IPAS-preconditioned medium (IPAS-CM) exerted neuroprotection. Furthermore, circSHOC2 expression was significantly upregulated in exosomes released from IPAS-CM. Overexpression of circSHOC2 in neurons yielded the same protective effects as those from IPAS-EXOs in vitro , and similar results were also observed in the middle cerebral artery occlusion (MCAO) mouse model. Mechanistically, circSHOC2 reduced neuronal apoptosis via regulating autophagy. Furthermore, circSHOC2 was found to sponge miR-7670-3p, which regulated SIRT1 expression. Transfection with an miR-7670-3p small interfering RNA (siRNA) (siRNA-7670-3p) and incubation with circSHOC2 extracellular vesicles attenuated ischemia-induced neuronal apoptosis in vivo and in vitro , while silencing of SIRT1 reversed the protective effects of exosomal circSHOC2 on hypoxic cerebral neurons. Taken together, our findings indicate that circSHOC2 in IPAS-EXOs suppressed neuronal apoptosis and ameliorated neuronal damage by regulating autophagy and acting on the miR-7670-3p/SIRT1 axis, which might contribute to a therapeutic strategy for ischemic stroke treatment.

Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

“…Recent studies have shown that abnormally expressed circRNAs may be involved in the pathogenesis of neonatal HIBD [ 48 ]. Furthermore, exosome-shuttled circRNAs have been shown to improve ischemic brain injury [ 49 ]. Therefore, it is worthwhile to investigate which circRNAs in MSC-exos inhibit microglial pyroptosis and ameliorate neuronal damage by regulating FOXO3a in our system.…”

Delivery of Therapeutic Agents to the Central Nervous System and the Promise of Extracellular Vesicles

“…Circular RNA (circRNA) have covalently connected 5′ and 3′ terminal ends, creating a closed long non-coding RNA (lncRNA) [ 151 ]. CircSHOC2, a circRNA transcribed from the SHOC2 gene, delivered in exosomes suppressed apoptosis and ameliorated neuronal damage in an ischemic stroke model by acting through the miR-7670-3p/SIRT1 pathway to regulate autophagy [ 152 ]. In this study, ischemic-preconditioned astrocyte-derived exosomes (IPAS-Exo) were used, as these exosomes were found to have significantly increased levels of CircSHOC2 caused by ischemic treatment.…”

Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy

“…Although excessive or insufficient levels of autophagy promote cell death, moderate levels are pro-survival in response to stressful circumstances [ 61 ]. Chen et al demonstrated that exosome-shuttled circSHOC2, a circular RNA from ischemic pre-conditioned astrocytes, reduces neuronal apoptosis by targeting the miR-7670-3p/sirtuin 1 (SIRT1) axis to promote autophagy [ 62 ]. Other As-Exo-derived miRs with similar effects are miR-361 and miR-34c.…”