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Molecular Neurobiology

, Volume 54, Issue 4, pp 2659–2673 | Cite as

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

  • Yi Zhang
  • Michael Chopp
  • Xian Shuang Liu
  • Mark Katakowski
  • Xinli Wang
  • Xinchu Tian
  • David Wu
  • Zheng Gang Zhang
Article

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

Exosomes Mesenchymal stromal cells Axon MicroRNA 

Notes

Acknowledgments

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

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Yi Zhang
    • 1
  • Michael Chopp
    • 1
    • 2
  • Xian Shuang Liu
    • 1
  • Mark Katakowski
    • 1
  • Xinli Wang
    • 1
  • Xinchu Tian
    • 3
  • David Wu
    • 3
  • Zheng Gang Zhang
    • 1
  1. 1.Department of Neurology, Henry Ford HospitalDetroitUSA
  2. 2.Department of PhysicsOakland UniversityRochesterUSA
  3. 3.Troy High SchoolTroyUSA

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