miRNA Exosomes Promote Myelination

[NHE]

What are exosomes and how can they be used in multiple sclerosis therapy?
Expert Rev Neurother. 2014 Apr;14(4):353-5.

• Current treatment options for multiple sclerosis are limited and consist of immunosuppressors or agents to prevent immune infiltration of the brain. These therapies have potentially harmful side effects and do little to promote myelin repair. Instead, we suggest using exosomes, naturally occurring small vesicles that exert influence through the delivery of mRNA, microRNA and protein. Dendritic cells can be cultured from bone marrow and stimulated to release exosomes. When administered to the brain, these exosomes significantly increase myelination and improve remyelination following injury by prompting preoligodendrocytes to differentiate into myelin producing cells. Additionally, they are non-toxic and can easily cross the blood-brain barrier and, thus, have great potential as a therapeutic.

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[NHE]

Remyelination: Are Exosomes Containing microRNA the Answer?
http://www.msdiscovery.org/news/new_fin ... rna-answer

Naturally produced exosomes with miRNA led to increased myelination in vitro and in vivo
Stephani Sutherland, Ph.D.

Today’s treatments for multiple sclerosis aim squarely at the immune system, not the sheath of myelin that insulates and nourishes axons. Eventually, MS destroys that protective layer formed by oligodendrocytes for good. But that could soon change with a new therapeutic strategy to remyelinate axons, currently under investigation by Richard Kraig, M.D., Ph.D., at the University of Chicago, Illinois.

Kraig’s team showed that naturally produced nano-sized vesicles called exosomes packed with microRNA (miRNA) led to increased myelination in healthy rats and remyelination in an in vitro model of demyelination. Kraig presented the work at the 2013 annual meeting of the Society for Neuroscience in San Diego, California. At a press conference there dedicated to MS research, he called the tiny vesicles “Mother Nature’s way of healing the brain.”

“The findings shown today represent real promise for the millions suffering from MS,” said press conference moderator Jeffrey Rothstein, M.D., Ph.D., who studies neurodegenerative disease at Johns Hopkins University in Baltimore, Maryland, and was not involved in the work. Despite many remaining questions, he told MSDF in an email, “miRNA represents a novel approach to [MS] therapeutics that certainly should be considered.”

Electron micrographs depict increased myelin in slice cultures following treatment with IFNγ-stimulated exosomes (right) compared to untreated control (left). From Pusic et al., 2014.

[NHE]

Environmental Enrichment Stimulates Immune Cell Secretion of Exosomes that Promote CNS Myelination and May Regulate Inflammation.
Cell Mol Neurobiol. 2016 Apr;36(3):313-325

• Environmental enrichment (EE) consists of increased physical, intellectual, and social activity, and has wide-ranging effects, including enhancing cognition, learning and memory, and motor coordination. Animal studies have demonstrated that EE improves outcome of brain trauma and neurodegenerative disorders, including demyelinating diseases like multiple sclerosis, making it a promising therapeutic option. However, the complexity of applying a robust EE paradigm makes clinical use difficult. A better understanding of the signaling involved in EE-based neuroprotection may allow for development of effective mimetics as an alternative. In prior work, we found that exosomes isolated from the serum of rats exposed to EE impact CNS myelination. Exosomes are naturally occurring nanovesicles containing mRNA, miRNA, and protein, which play important roles in cell function, disease, and immunomodulation. When applied to hippocampal slice cultures or nasally administered to naïve rats, EE-serum exosomes significantly increase myelin content, oligodendrocyte precursor (OPC) and neural stem cell levels, and reduce oxidative stress (OS). We found that rat EE exosomes were enriched in miR-219, which is necessary and sufficient for OPC differentiation into myelinating cells. Thus, peripherally produced exosomes may be a useful therapy for remyelination. Here, we aim to better characterize the impact of EE on CNS health and to determine the cellular source of nutritive exosomes found in serum. We found that exosomes isolated from various circulating immune cell types all increased slice culture myelin content, contained miR-219, and reduced OS, suggesting that EE globally alters immune function in a way that supports brain health.

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