Abstract
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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Acknowledgments
This work was supported by the National Institutes of Health Common Fund, through the Office of Strategic Coordination/Office of the Director (5UH2 TR000918-02, 4UH3TR000918-03, 3UH2 TR000918-02S1, and 3UH3TR000918-03S1), core facilities funds from the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1 TR000430), the National Institute of Neurological Disorders and Stroke (NS-019108), and the National Institute of Child Health and Human Disorders (5PO1 HD-09402). We thank Dr. Lisa Won and Jason Schumer for reading and commenting on the manuscript. We also thank Dr. Y. Chen for assistance with immunostaining and electron microscopy. Electron microscopy was performed at the University of Chicago Electron Microscopy Facility.
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The authors report a patent pending entitled, “Exosomes-Based Therapeutics Against Neurodegenerative Disorders” that involves exosomes containing microRNA that promote myelination and prevent spreading depression.
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Kae M. Pusic and Aya D. Pusic contributed equally to this work.
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Pusic, K.M., Pusic, A.D. & Kraig, R.P. Environmental Enrichment Stimulates Immune Cell Secretion of Exosomes that Promote CNS Myelination and May Regulate Inflammation. Cell Mol Neurobiol 36, 313–325 (2016). https://doi.org/10.1007/s10571-015-0269-4
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DOI: https://doi.org/10.1007/s10571-015-0269-4