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Mol Neurobiol. 2017 May;54(4):2659-2673. doi: 10.1007/s12035-016-9851-0. Epub 2016 Mar 19.

Exosomes Derived from Mesenchymal Stromal Cells Promote Axonal Growth of Cortical Neurons.

Author information

1
Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA.
2
Department of Physics, Oakland University, Rochester, MI, 48309, USA.
3
Troy High School, Troy, MI, 48098, USA.
4
Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA. zhazh@neuro.hfh.edu.

Abstract

Treatment of brain injury with exosomes derived from mesenchymal stromal cells (MSCs) enhances neurite growth. However, the direct effect of exosomes on axonal growth and molecular mechanisms underlying exosome-enhanced neurite growth are not known. Using primary cortical neurons cultured in a microfluidic device, we found that MSC-exosomes promoted axonal growth, whereas attenuation of argonaut 2 protein, one of the primary microRNA (miRNA) machinery proteins, in MSC-exosomes abolished their effect on axonal growth. Both neuronal cell bodies and axons internalized MSC-exosomes, which was blocked by botulinum neurotoxins (BoNTs) that cleave proteins of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Moreover, tailored MSC-exosomes carrying elevated miR-17-92 cluster further enhanced axonal growth compared to native MSC-exosomes. Quantitative RT-PCR and Western blot analysis showed that the tailored MSC-exosomes increased levels of individual members of this cluster and activated the PTEN/mTOR signaling pathway in recipient neurons, respectively. Together, our data demonstrate that native MSC-exosomes promote axonal growth while the tailored MSC-exosomes can further boost this effect and that tailored exosomes can deliver their selective cargo miRNAs into and activate their target signals in recipient neurons. Neuronal internalization of MSC-exosomes is mediated by the SNARE complex. This study reveals molecular mechanisms that contribute to MSC-exosome-promoted axonal growth, which provides a potential therapeutic strategy to enhance axonal growth.

KEYWORDS:

Axon; Exosomes; Mesenchymal stromal cells; MicroRNA

PMID:
26993303
PMCID:
PMC5028236
DOI:
10.1007/s12035-016-9851-0
[Indexed for MEDLINE]
Free PMC Article

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