title: Exosomes Derived from Mesenchymal Stromal Cells Promote Axonal Growth of Cortical Neurons.
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.
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA.|Department of Physics, Oakland University, Rochester, MI, 48309, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA.
authors.forename: Xian Shuang
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Katakowski
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Troy High School, Troy, MI, 48098, USA.
authors.forename: Xinchu
authors.initials: X
authors.lastname: Tian
authors.affiliation: Troy High School, Troy, MI, 48098, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Neurology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA. zhazh@neuro.hfh.edu.
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D001905:Botulinum Toxins / Q000633:toxicity; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D050600:SNARE Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C582332:Ago2 protein, rat; D060565:Argonaute Proteins; D011508:Chondroitin Sulfate Proteoglycans; D035683:MicroRNAs; D050600:SNARE Proteins; D001905:Botulinum Toxins
keywords: Axon; Exosomes; Mesenchymal stromal cells; MicroRNA