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Dendritic-Cell-Derived Exosomes As Possible Therapy for Multiple Sclerosis--Neuroscience 2013

Currently, no multiple sclerosis (MS) treatments promote remyelination. Richard Kraig, M.D., Ph.D., Professor in Neurosciences and Director of the Migraine Headache Clinic at the University of Chicago Medicine, described to the press on Sunday, May 10, at the Society for Neuroscience 2013 meeting in San Diego, his group’s new work showing that dendritic cells, a type of immune cell present in blood, can be cultured from bone marrow and stimulated to release small particles called exosomes (see image). When administered to the brain, these exosomes significantly increase myelination and improve remyelination following a demyelinating injury, like that caused by MS. MS is an inflammatory disease involving oligodendrocyte loss, demyelination, and failure to remyelinate damaged brain areas. Oligodendrocytes in the central nervous system produce myelin, the insulation surrounding axons, which is necessary for neuronal signaling. Damage to oligodendrocytes and demyelination — loss of this insulation — can lead to severe neurological disability. Remyelination is a spontaneously occurring repair process mediated by recruitment of oligodendrocyte precursor cells to damaged areas. Their subsequent differentiation into mature oligodendrocytes is capable of replacing lost myelin. Initially, MS patients follow a relapsing-remitting disease course, characterized by periods of partial recovery associated with incomplete remyelination. However, over time this ability to repair declines and patients develop a secondary-progressive, steadily worsening disease course. With over 400,000 people currently suffering from MS in the United States, it is a significant and devastating healthcare burden. Recent evidence shows that linking the circulatory system of an aged animal to a young one improves the aged partner’s recovery from a demyelinating injury. Dr. Kraig and colleagues have previously shown that this effect likely involves production of exosomes that impact oligodendrocyte development and production of myelin. Exosomes are exported by many cell types and have the potential for targeting specific cells to deliver their cargo of proteins, mRNA, and importantly, microRNA. MicroRNAs are small non-coding RNA molecules that are increasingly recognized for their role in regulating gene expression. Dr. Kraig and his team found that interferon gamma (IFNγ)-stimulated, dendritic cell-derived exosomes increase baseline myelination. In addition, the exosomes improve recovery from MS modeled by inducing demyelination. Furthermore, when nasally administered to whole animals, these exosomes stimulate an increase in brain myelin. All this suggests that these nutritive exosomes can be crafted into a novel therapy for MS. Dr. Kraig is interested in better understanding why and how these exosomes improve myelination. Studies to determine the content of IFNγ-stimulated, dendritic cell-derived exosomes are ongoing in his laboratory. To date, his team has found high levels of a microRNA species known to facilitate oligodendrocyte precursor differentiation into mature cells that are capable of producing myelin. Additional microRNA species involved in increasing oxidative tolerance are also present at high levels in stimulated exosomes. These microRNAs may be responsible for the reduced oxidative stress and increased antioxidant levels observed in the exosome-treated brain. Dr. Kraig believes reduction of oxidative stress also plays a role in remyelination, because antioxidants protect oligodendrocytes and enhance their production of myelin. Additionally, IFNγ-stimulated dendritic cell-derived exosomes are preferentially taken up by oligodendrocytes, suggesting that they directly stimulate these cells. This proof-of-principal work paves the way for further development of dendritic cell-derived exosomes as a remyelination therapy. Future directions include re-engineering exosomes to contain only desired microRNAs and optimizing targeting methods to direct them to specific cells. Treatment options for MS are limited and consist of immunosuppressors or agents to prevent immune infiltration of the brain. These therapies potentially have harmful side effects, and do little to promote myelin repair. Instead, Dr. Kraig suggests using exosomes, naturally occurring vesicles that exert influence through delivery of mRNAs, microRNAs, and proteins. They are a non-toxic, ideal delivery platform that can easily cross the blood brain barrier, and have great potential as an adjunct approach to increasing remyelination post-injury. Thus, Dr. Kraig believes that his group’s results show great potential for use of these exosomes as a potential therapeutic to promote remyelination in MS. Research was supported with funds from the National Institutes of Health. This summary of Dr. Kraig’s research was provided by the Society for Neuroscience, together with the press release on MS advances issued on Sunday, November 10. The formal scientific presentation of Dr. Kraig’s work will be given on Wednesday, November 13, in the period 2 pm - 3 pm PST. The Society for Neuroscience 2013 meeting runs through November 13, 2013. [Society for Neuroscience program] [Society for Neuroscience 2013 meeting]