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Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation.

ABSTRACT: Although adipose derived stem cells (ADSCs) exert their therapeutic potential in ischemic stroke, the migration of ADSCs in injured area is not apparently observed after intravenous administration. ADSCs are an important source of exosomes which hold great promise as an endogenous drug delivery system for the treatment of cerebral ischemia given their ability to cross the blood-brain barrier. Here we investigated whether ADSCs-derived exosomes mediated miRNAs transfer and thus promoted neurological recovery after stroke. We first proved that miR-126 levels were reduced in patients' plasma with acute ischemic stroke and in rat plasma and brain tissue after ischemia. To test the effect of exosomal miR-126, we employed overexpression and knock-down technologies to up-regulate or inhibit miR-126 level in ADSCs and thus acquired miR-126+ exosomes and miR-126- exosomes, respectively. Compared with control, systemic administration of ADSCs-derived exosomes significantly increased the expression of von Willebrand factor (an endothelia cell marker) and doublecortin (a neuroblasts marker) and improved functional recovery in stroke rats. ADSCs-derived exosomes also resulted in a decrease of neuron cell death and an increase of cell proliferation compared with control. Importantly, these outcomes were further enhanced with miR-126+ exosomes treatment and were significantly decreased with miR-126- exosomes treatment, compared to naïve exosomes treatment. MiR-126+ exosomes also inhibited microglial activation and the expression of inflammatory factors in vivo and in vitro. Our results suggest that intravenous administration of miR-126+ exosomes post stroke improves functional recovery, enhances neurogenesis, inhibits neuroinflammation, and represents a novel treatment for stroke.

SUBMITTER: Geng W

PROVIDER: S-EPMC6413259 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation.

Geng Wujun W Tang Hongli H Luo Shan S Lv Ya Y Liang Dongdong D Kang Xianhui X Hong Wandong W

American journal of translational research 20190215 2

Although adipose derived stem cells (ADSCs) exert their therapeutic potential in ischemic stroke, the migration of ADSCs in injured area is not apparently observed after intravenous administration. ADSCs are an important source of exosomes which hold great promise as an endogenous drug delivery system for the treatment of cerebral ischemia given their ability to cross the blood-brain barrier. Here we investigated whether ADSCs-derived exosomes mediated miRNAs transfer and thus promoted neurologi ...[more]

PMID: 30899379

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Project description:Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106-126 (PrP(106-126)). We first examined the time course of CD36 mRNA expression upon exposure to PrP(106-126) in BV2 microglia. We then analyzed different parameters of microglial activation in PrP(106-126)-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP(106-126). The results showed that PrP(106-126) treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1?, IL-6 and TNF-?), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-?B and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP(106-126)-stimulated NF-?B activation and TNF-? protein release, abrogated the PrP(106-126)-induced iNOS stimulation, downregulated IL-1? and IL-6 expression at both mRNA and protein levels as well as TNF-? mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP(106-126)-treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP(106-126). Together, these results suggest that CD36 is involved in PrP(106-126)-induced microglial activation and that the participation of CD36 in the interaction between PrP(106-126) and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling.

Dataset Information

Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation.

Publications

Exosomes from miRNA-126-modified ADSCs promotes functional recovery after stroke in rats by improving neurogenesis and suppressing microglia activation.

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