IFNγ Stimulated dendritic cell exosomes as a therapeutic for remyelination
Wednesday, Nov 13, 2013, 2:00 PM - 3:00 PM
*A. D. PUSIC
, K. M. PUSIC
, R. P. KRAIG
Dept. of Neurol.,
Univ. of Chicago, Chicago, IL
Multiple sclerosis (MS) is an inflammatory disorder involving myelin damage and oligodendrocyte loss. Treatment options are limited and consist of conventional immunosuppressors, immunomodulators, or agents to prevent lymphocyte infiltration to the CNS . These therapies can induce harmful immune sequelae and do little to promote repair. Instead, we suggest use of exosomes, naturally occurring nanovesicles (40-100nm) that play important roles in physiologic cell function, disease states, and modulation of the immune system. While their exact function in these diverse activities is not yet fully understood, they exert influence through delivery of mRNAs, miRNAs 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. Exosomes are produced by most cells, and their composition differs based on cell type and state. Dendritic cells (DCs), professional antigen presenting cells, are a rich source of exosomes in vivo, which can be scalable in vitro .
Here, we stimulated primary DC cultures with low-level IFNγ, as phasic low-level IFNγ significantly increases myelination when applied to brain slice cultures or when administered nasally (Pusic, unpublished). When applied to slice cultures, exosomes released by IFNγ-stimulated DCs increased baseline myelination, reduced oxidative stress, and improved remyelination following acute lysolecithin-induced demyelination. These effects were not seen when exosomes from unstimulated DCs were administered. Similarly, nasal administration of IFNγ-stimulated DC exosomes increased CNS myelination in vivo, whereas unstimulated DC exosomes did not. Screening of miRNA content of DC exosomes revealed significant differences in IFNγ-stimulated versus unstimulated conditions. Among these changes, we observed that IFNγ-stimulated exosomes were enriched with miR-219, which is necessary and sufficient for oligodendrocyte differentiation into myelinating cells .
Tracking studies revealed differences in uptake. Whereas unstimlated DC exosomes were taken up mainly by astrocytes and microglia, IFNγ-stimulated DC exosomes were preferentially taken up by oligodendrocytes. This is an important first step in elucidating the mechanism of DC exosome-mediated increase in myelin that will aid in the development of these exosomes as a therapy for remyelination. (*These authors contributed equally to this work.)
 Tullman et al., (2013) Am J Manag Care;
 Bobrie et al., (2011) Traffic;
 Yin et al., (2013) Inflammation;
 Dugas et al., (2010) Neuron.
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