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

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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.

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Acknowledgments

This work was supported by National Institutes of Health (RO1 NS088656 and RO1 NS75156).

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Authors and Affiliations

  1. Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA

    Yi Zhang, Michael Chopp, Xian Shuang Liu, Mark Katakowski, Xinli Wang & Zheng Gang Zhang

  2. Department of Physics, Oakland University, Rochester, MI, 48309, USA

    Michael Chopp

  3. Troy High School, Troy, MI, 48098, USA

    Xinchu Tian & David Wu

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  1. Yi Zhang
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Zhang, Y., Chopp, M., Liu, X.S. et al. Exosomes Derived from Mesenchymal Stromal Cells Promote Axonal Growth of Cortical Neurons. Mol Neurobiol 54, 2659–2673 (2017). https://doi.org/10.1007/s12035-016-9851-0

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