Exosomes: A New Weapon to Treat the Central Nervous System

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.

[1]  Laurence Zitvogel,et al.  Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes , 1998, Nature Medicine.

[2]  R. Tompkins,et al.  Bone Marrow Mesenchymal Stromal Cells Attenuate Organ Injury Induced by LPS and Burn , 2010, Cell transplantation.

[3]  M. Kas,et al.  Intranasal Mesenchymal Stem Cell Treatment for Neonatal Brain Damage: Long-Term Cognitive and Sensorimotor Improvement , 2013, PloS one.

[4]  Dongmei Sun,et al.  A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[5]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[6]  W. Pardridge,et al.  Intravenous RNA Interference Gene Therapy Targeting the Human Epidermal Growth Factor Receptor Prolongs Survival in Intracranial Brain Cancer , 2004, Clinical Cancer Research.

[7]  F. Benfenati,et al.  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 , 2011, The Journal of Neuroscience.

[8]  M. Wassef,et al.  The particles of the embryonic cerebrospinal fluid: How could they influence brain development? , 2008, Brain Research Bulletin.

[9]  A. Kavelaars,et al.  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 , 2010, The Journal of Neuroscience.

[10]  A. Boer,et al.  Strategies to Improve Drug Delivery Across the Blood-Brain Barrier , 2007, Clinical pharmacokinetics.

[11]  Clotilde Théry,et al.  Exosome Secretion: Molecular Mechanisms and Roles in Immune Responses , 2011, Traffic.

[12]  J. Wrana,et al.  Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration , 2012, Cell.

[13]  Ç. Gerçel-Taylor,et al.  Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments , 2011, Seminars in Immunopathology.

[14]  Huaxi Xu,et al.  Insulin-degrading enzyme sorting in exosomes: a secretory pathway for a key brain amyloid-beta degrading protease. , 2010, Journal of Alzheimer's disease : JAD.

[15]  A. McKee,et al.  Exosome-associated Tau Is Secreted in Tauopathy Models and Is Selectively Phosphorylated in Cerebrospinal Fluid in Early Alzheimer Disease* , 2011, The Journal of Biological Chemistry.

[16]  T. Kislinger,et al.  Cancer Cells Induced to Express Mesenchymal Phenotype Release Exosome-like Extracellular Vesicles Carrying Tissue Factor* , 2012, The Journal of Biological Chemistry.

[17]  F. Sánchez‐Madrid,et al.  Intercellular communication: diverse structures for exchange of genetic information , 2012, Nature Reviews Molecular Cell Biology.

[18]  Sébastien A. Gauthier,et al.  The Exosome Secretory Pathway Transports Amyloid Precursor Protein Carboxyl-terminal Fragments from the Cell into the Brain Extracellular Space* , 2012, The Journal of Biological Chemistry.

[19]  J. Huwyler,et al.  Brain drug delivery of small molecules using immunoliposomes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Ntzouni,et al.  Cell-Produced α-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival , 2010, The Journal of Neuroscience.

[21]  A. Levine,et al.  The regulation of exosome secretion: a novel function of the p53 protein. , 2006, Cancer research.

[22]  G. Raposo,et al.  Accumulation of Major Histocompatibility Complex Class Ii Molecules in Mast Cell Secretory Granules and Their Release upon Degranulation Generation of Bmmcs Preparation of B Cells Reagents and Monoclonal Antibodies (mabs) Immunofluorescence Staining and Confocal Microscopy Pulse-chase# Labeling and , 2022 .

[23]  Yi Li,et al.  Exosome‐Mediated Transfer of miR‐133b from Multipotent Mesenchymal Stromal Cells to Neural Cells Contributes to Neurite Outgrowth , 2012, Stem cells.

[24]  Dongmei Sun,et al.  Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[25]  Laurence Zitvogel,et al.  Molecular Characterization of Dendritic Cell-Derived Exosomes , 1999, The Journal of cell biology.

[26]  Changjin Lee,et al.  Exosomes Mediate the Cytoprotective Action of Mesenchymal Stromal Cells on Hypoxia-Induced Pulmonary Hypertension , 2012, Circulation.

[27]  Gerard Pasterkamp,et al.  Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. , 2010, Stem cell research.

[28]  D. Terrian,et al.  Senescence-associated exosome release from human prostate cancer cells. , 2008, Cancer research.

[29]  G. Lachenal,et al.  Exosomes are released by cultured cortical neurones , 2006, Molecular and Cellular Neuroscience.

[30]  M Chopp,et al.  Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia , 2001, Neuroscience.

[31]  J. Marine,et al.  Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice , 2008, Cell Death and Differentiation.

[32]  S. Lim,et al.  Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs , 2011, Journal of Translational Medicine.

[33]  C. Masters,et al.  Inhibition of γ‐secretase causes increased secretion of amyloid precursor protein C‐terminal fragments in association with exosomes , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  Fan Yang,et al.  Mesenchymal stem cells arrest intervertebral disc degeneration through chondrocytic differentiation and stimulation of endogenous cells. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[35]  A. Parini,et al.  Intraparenchymal Injection of Bone Marrow Mesenchymal Stem Cells Reduces Kidney Fibrosis after Ischemia-Reperfusion in Cyclosporine-Immunosuppressed Rats , 2012, Cell transplantation.

[36]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[37]  M. Wood,et al.  Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes , 2011, Nature Biotechnology.

[38]  M. Chopp,et al.  Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery , 2002, Neurology.

[39]  A. Régnault,et al.  TCR Activation of Human T Cells Induces the Production of Exosomes Bearing the TCR/CD3/ζ Complex1 , 2002, The Journal of Immunology.

[40]  Hamid Cheshmi Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[41]  G. Remuzzi,et al.  Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. , 2013, Stem cells and development.

[42]  W. Grizzle,et al.  Abstract 4446: A novel nanoparticle drug delivery system: The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes , 2011 .

[43]  F. Castellino,et al.  Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. , 2007, Blood.

[44]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[45]  J. Rothstein,et al.  Neuronal Exosomal miRNA-dependent Translational Regulation of Astroglial Glutamate Transporter GLT1* , 2013, The Journal of Biological Chemistry.

[46]  Gema Moreno-Bueno,et al.  Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2012, Nature Medicine.

[47]  M. Johansson,et al.  Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells , 2011, Proceedings of the National Academy of Sciences.

[48]  O. Lindvall,et al.  Neuronal replacement from endogenous precursors in the adult brain after stroke , 2002, Nature Medicine.

[49]  A. Hill,et al.  Enrichment of prion protein in exosomes derived from ovine cerebral spinal fluid. , 2008, Veterinary immunology and immunopathology.

[50]  M. Adam,et al.  Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes , 1985, The Journal of cell biology.

[51]  E. Nabel,et al.  Gene transfer in vivo with DNA-liposome complexes: safety and acute toxicity in mice. , 1992, Human gene therapy.

[52]  M. Pittenger,et al.  Mesenchymal stem cells and their potential as cardiac therapeutics. , 2004, Circulation research.

[53]  M. Campiglio,et al.  Potential role of HER2‐overexpressing exosomes in countering trastuzumab‐based therapy , 2012, Journal of cellular physiology.

[54]  G. Raposo,et al.  BCR‐bound antigen is targeted to exosomes in human follicular lymphoma B‐cells 1 , 2006, Biology of the cell.

[55]  Alzheimer's disease beta-amyloid peptides are released in association with exosomes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Q. Lu,et al.  MicroRNA-Mediated Control of Oligodendrocyte Differentiation , 2010, Neuron.

[57]  Laurence Zitvogel,et al.  Exosomes: composition, biogenesis and function , 2002, Nature Reviews Immunology.

[58]  Peter J. Peters,et al.  Molecules relevant for T cell‐target cell interaction are present in cytolytic granules of human T lymphocytes , 1989, European journal of immunology.