Adipose‐derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR‐25

Abstract

Grafted mesenchymal stem cells (MSCs) yield neuroprotection in preclinical stroke models by secreting extracellular vesicles (EVs). The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such cargo and its underlying mechanism, primary neurons were exposed to oxygen‐glucose‐deprivation (OGD) and cocultured with adipose‐derived MSCs (ADMSCs) or ADMSC‐secreted EVs. Under such conditions, both ADMSCs and ADMSC‐secreted EVs significantly reduced neuronal death. Screening for signalling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53‐BNIP3 activity in neurons receiving either treatment paradigm. However, the aforementioned effects were reversed when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869 or when Hrs was knocked down. In light of miR‐25‐3p being the most highly expressed miRNA in ADMSC‐EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Indeed, a miR‐25‐3p oligonucleotide mimic reduced cell death, whereas the anti‐oligonucleotide increased autophagic flux and cell death by modulating p53‐BNIP3 signalling in primary neurons exposed to OGD. Likewise, native ADMSC‐EVs but not EVs obtained from ADMSCs pretreated with the anti‐miR‐25‐3p oligonucleotide (ADMSC‐EVsanti‐miR‐25‐3p) confirmed the aforementioned in vitro observations in C57BL/6 mice exposed to cerebral ischemia. The infarct size was reduced, and neurological recovery was increased in mice treated with native ADMSC‐EVs when compared to ADMSC‐EVsanti‐miR‐25‐3p. ADMSCs induce neuroprotection by improved autophagic flux through secreted EVs containing miR‐25‐3p. Hence, our work uncovers a novel key factor in naturally secreted ADMSC‐EVs for the regulation of autophagy and induction of neuroprotection in a preclinical stroke model.

A Comprehensive Genomic Analysis Constructs miRNA–mRNA Interaction Network in Hepatoblastoma

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The role of small extracellular vesicles in cerebral and myocardial ischemia—Molecular signals, treatment targets, and future clinical translation

“…Previous work from our group in a model of focal cerebral ischemia in mice demonstrated that AD-MSC-EVs transfer miRNA-25, modulating autophagy in ischemic neurons by targeting BNIP3, which results in increased cell viability. 45 Likewise, Xin et al also reported in a model of focal cerebral ischemia in rats that BM-MSCs transfer miR-133b to neurons via EVs to increase neurite branch numbers and total neurite length under ischemic conditions. 46 The authors observed that miR-133b concentrations in EVs were increased when MSCs were pretreated with ischemic brain extracts in vitro before usage.…”

Understanding the Pathophysiology of Exosomes in Schistosomiasis: A New Direction for Disease Control and Prevention

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