Skip to main content

Advertisement

SpringerLink
Log in

Exosomes: A New Weapon to Treat the Central Nervous System

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The potential of exosomes to treat central nervous system (CNS) pathologies has been recently demonstrated. These studies make way for a complete new field that aims to exploit the natural characteristics of these vesicles, considered for a long time as side products of physiological cellular pathways. Recently, however, the biological significance of exosomes has been evaluated and exosomes can now be viewed upon as new relevant functional entities for development of novel therapeutic strategies. In this review, we aim to summarize the state-of-the-art role of exosomes in the CNS and to speculate about possible future therapeutic applications of exosomes. In particular, we will speculate about the use of these vesicles as a substitute of cell-based therapies for the treatment of brain damage and review the potential of exosomes as drug delivery vehicles for the CNS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579

    CAS  PubMed  Google Scholar 

  2. Mittelbrunn M, Sanchez-Madrid F (2012) Intercellular communication: diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol 13:328–335

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    Article  CAS  PubMed  Google Scholar 

  4. Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593

    Article  CAS  PubMed  Google Scholar 

  5. Raposo G, Tenza D, Mecheri S, Peronet R, Bonnerot C, Desaymard C (1997) Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol Biol Cell 8:2631–2645

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4:594–600

    Article  CAS  PubMed  Google Scholar 

  7. Bhatnagar S, Shinagawa K, Castellino FJ, Schorey JS (2007) Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 110:3234–3244

    Article  CAS  PubMed  Google Scholar 

  8. Pan BT, Teng K, Wu C, Adam M, Johnstone RM (1985) Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 101:942–948

    Article  CAS  PubMed  Google Scholar 

  9. Peters PJ, Geuze HJ, Van der Donk HA, Slot JW, Griffith JM, Stam NJ, Clevers HC, Borst J (1989) Molecules relevant for T cell-target cell interaction are present in cytolytic granules of human T lymphocytes. Eur J Immunol 19:1469–1475

    Article  CAS  PubMed  Google Scholar 

  10. Blanchard N, Lankar D, Faure F, Regnault A, Dumont C, Raposo G, Hivroz C (2002) TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol 168:3235–3241

    CAS  PubMed  Google Scholar 

  11. Rialland P, Lankar D, Raposo G, Bonnerot C, Hubert P (2006) BCR-bound antigen is targeted to exosomes in human follicular lymphoma B-cells. Biol Cell 98:491–501

    Article  CAS  PubMed  Google Scholar 

  12. Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147:599–610

    Article  CAS  PubMed  Google Scholar 

  13. Yu X, Harris SL, Levine AJ (2006) The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res 66:4795–4801

    Article  CAS  PubMed  Google Scholar 

  14. Lehmann BD, Paine MS, Brooks AM, McCubrey JA, Renegar RH, Wang R, Terrian DM (2008) Senescence-associated exosome release from human prostate cancer cells. Cancer Res 68:7864–7871

    Article  CAS  PubMed  Google Scholar 

  15. Lespagnol A, Duflaut D, Beekman C, Blanc L, Fiucci G, Marine JC, Vidal M, Amson R, Telerman A (2008) Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death Differ 15:1723–1733

    Article  CAS  PubMed  Google Scholar 

  16. Bobrie A, Colombo M, Raposo G, Thery C (2011) Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12:1659–1668

    Article  CAS  PubMed  Google Scholar 

  17. Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, Morelli D, Villa A, Della MP, Menard S, Filipazzi P, Rivoltini L, Tagliabue E, Pupa SM (2012) Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol 227:658–667

    Article  CAS  PubMed  Google Scholar 

  18. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Garnier D, Magnus N, Lee TH, Bentley V, Meehan B, Milsom C, Montermini L, Kislinger T, Rak J (2012) Cancer cells induced to express mesenchymal phenotype release exosome-like extracellular vesicles carrying tissue factor. J Biol Chem 287:43565–43572

    Article  CAS  PubMed  Google Scholar 

  20. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151:1542–1556

    Article  CAS  PubMed  Google Scholar 

  21. Faure J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, Grange J, Schoehn G, Goldberg Y, Boyer V, Kirchhoff F, Raposo G, Garin J, Sadoul R (2006) Exosomes are released by cultured cortical neurones. Mol Cell Neurosci 31:642–648

    Article  CAS  PubMed  Google Scholar 

  22. Taylor DD, Gercel-Taylor C (2011) Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 33:441–454

    Article  CAS  PubMed  Google Scholar 

  23. Vella LJ, Greenwood DL, Cappai R, Scheerlinck JP, Hill AF (2008) Enrichment of prion protein in exosomes derived from ovine cerebral spinal fluid. Vet Immunol Immunopathol 124:385–393

    Article  CAS  PubMed  Google Scholar 

  24. Bachy I, Kozyraki R, Wassef M (2008) The particles of the embryonic cerebrospinal fluid: how could they influence brain development? Brain Res Bull 75:289–294

    Article  CAS  PubMed  Google Scholar 

  25. Wang S, Cesca F, Loers G, Schweizer M, Buck F, Benfenati F, Schachner M, Kleene R (2011) Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. J Neurosci 31:7275–7290

    Article  CAS  PubMed  Google Scholar 

  26. Xin H, Li Y, Buller B, Katakowski M, Zhang Y, Wang X, Shang X, Zhang ZG, Chopp M (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30:1556–1564

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, Rothstein J, Yang Y (2013) Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem 288:7105–7116

    Article  CAS  PubMed  Google Scholar 

  28. Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K (2006) Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A 103:11172–11177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Sharples RA, Vella LJ, Nisbet RM, Naylor R, Perez K, Barnham KJ, Masters CL, Hill AF (2008) Inhibition of gamma-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J 22:1469–1478

    Article  CAS  PubMed  Google Scholar 

  30. Bulloj A, Leal MC, Xu H, Castano EM, Morelli L (2010) Insulin-degrading enzyme sorting in exosomes: a secretory pathway for a key brain amyloid-beta degrading protease. J Alzheimers Dis 19:79–95

    PubMed  Google Scholar 

  31. Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NC, Hall GF (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287:3842–3849

    Article  CAS  PubMed  Google Scholar 

  32. Perez-Gonzalez R, Gauthier SA, Kumar A, Levy E (2012) The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J Biol Chem 287:43108–43115

    Article  CAS  PubMed  Google Scholar 

  33. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30:6838–6851

    Article  CAS  PubMed  Google Scholar 

  34. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Svensson KJ, Kucharzewska P, Christianson HC, Skold S, Lofstedt T, Johansson MC, Morgelin M, Bengzon J, Ruf W, Belting M (2011) Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proc Natl Acad Sci U S A 108:13147–13152

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Huwyler J, Wu D, Pardridge WM (1996) Brain drug delivery of small molecules using immunoliposomes. Proc Natl Acad Sci U S A 93:14164–14169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Zhang Y, Zhang YF, Bryant J, Charles A, Boado RJ, Pardridge WM (2004) Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin Cancer Res 10:3667–3677

    Article  CAS  PubMed  Google Scholar 

  38. de Boer AG, Gaillard PJ (2007) Strategies to improve drug delivery across the blood–brain barrier. Clin Pharmacokinet 46:553–576

    Article  PubMed  Google Scholar 

  39. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345

    Article  CAS  PubMed  Google Scholar 

  40. Stewart MJ, Plautz GE, Del Buono L, Yang ZY, Xu L, Gao X, Huang L, Nabel EG, Nabel GJ (1992) Gene transfer in vivo with DNA-liposome complexes: safety and acute toxicity in mice. Hum Gene Ther 3:267–275

    Article  CAS  PubMed  Google Scholar 

  41. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang HG (2010) A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 18:1606–1614

    Article  CAS  PubMed  Google Scholar 

  42. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman L, Miller D, Zhang HG (2011) Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 19:1769–1779

    Article  CAS  PubMed  Google Scholar 

  43. Alfarano C, Roubeix C, Chaaya R, Ceccaldi C, Calise D, Mias C, Cussac D, Bascands JL, Parini A (2012) Intraparenchymal injection of bone marrow mesenchymal stem cells reduces kidney fibrosis after ischemia-reperfusion in cyclosporine-immunosuppressed rats. Cell Transplant 21(9):2009–2019

    Article  CAS  PubMed  Google Scholar 

  44. Yagi H, Soto-Gutierrez A, Kitagawa Y, Tilles AW, Tompkins RG, Yarmush ML (2010) Bone marrow mesenchymal stromal cells attenuate organ injury induced by LPS and burn. Cell Transplant 19:823–830

    Article  PubMed Central  PubMed  Google Scholar 

  45. Yang F, Leung VY, Luk KD, Chan D, Cheung KM (2009) Mesenchymal stem cells arrest intervertebral disc degeneration through chondrocytic differentiation and stimulation of endogenous cells. Mol Ther 17:1959–1966

    Article  CAS  PubMed  Google Scholar 

  46. Pittenger MF, Martin BJ (2004) Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95:9–20

    Article  CAS  PubMed  Google Scholar 

  47. Li Y, Chen J, Chen XG, Wang L, Gautam SC, Xu YX, Katakowski M, Zhang LJ, Lu M, Janakiraman N, Chopp M (2002) Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59:514–523

    Article  CAS  PubMed  Google Scholar 

  48. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ (2010) Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function. J Neurosci 30:9603–9611

    Article  PubMed  Google Scholar 

  49. Donega V, van Velthoven CT, Nijboer CH, van Bel F, Kas MJ, Kavelaars A, Heijnen CJ (2013) Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement. PLoS One 8:e51253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, Capelli C, Introna M, Remuzzi G, Benigni A (2013) Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev 22:772–780

    Article  CAS  PubMed  Google Scholar 

  51. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222

    Article  CAS  PubMed  Google Scholar 

  52. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E, Konstantinou G, Sdrimas K, Fernandez-Gonzalez A, Kourembanas S (2012) Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 126:2601–2611

    Article  CAS  PubMed  Google Scholar 

  53. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710

    Article  CAS  PubMed  Google Scholar 

  54. Zhang RL, Zhang ZG, Zhang L, Chopp M (2001) Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105:33–41

    Article  CAS  PubMed  Google Scholar 

  55. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963–970

    Article  CAS  PubMed  Google Scholar 

  56. Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Choo AB, Padmanabhan J, Lee CN, de Kleijn DP, Lim SK (2011) Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med 9:47

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Zhao X, He X, Han X, Yu Y, Ye F, Chen Y, Hoang T, Xu X, Mi QS, Xin M, Wang F, Appel B, Lu QR (2010) MicroRNA-mediated control of oligodendrocyte differentiation. Neuron 65:612–626

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgment

This study was supported in part by EU-7 Neurobid (HEALTH-F2-2009-241778) from the European Union.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Laboratory for Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, Lundlaan 6, 3584EA, Utrecht, The Netherlands

    Luca Braccioli, Cindy van Velthoven & Cobi J. Heijnen

  2. Department of Cell Biology, University Medical Center Utrecht, AZU Room G02.529, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands

    Luca Braccioli

  3. Department of Symptom research, MD Anderson Cancer Center, Laboratory of Neuroimmunology of Cancer-related Symptoms (NICRS); Institute of Biosciences and Technology, University of Texas, FCT10.0016; 2121 W. Holcombe Boulevard, Houston, TX, 77030, USA

    Cobi J. Heijnen

Authors
  1. Luca Braccioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cindy van Velthoven
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cobi J. Heijnen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cobi J. Heijnen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Braccioli, L., van Velthoven, C. & Heijnen, C.J. Exosomes: A New Weapon to Treat the Central Nervous System. Mol Neurobiol 49, 113–119 (2014). https://doi.org/10.1007/s12035-013-8504-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-013-8504-9

Keywords

Search

Navigation