Youth and environmental enrichment generate serum exosomes containing miR‐219 that promote CNS myelination

Abstract

Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression. However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cells—both under control conditions and after acute demyelination. Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination.

The systemic milieu as a mediator of dietary influence on stem cell function during ageing

“…The study by Pusic and Kraig (2014) provides proof of principle that environmental exposures can alter the circulating levels of key factors that alter stem cell function. The profound effect of both age and diet in altering stem cell function, coupled to growing appreciation of the impact of the systemic environment, indicates that age-and diet-induced effects on organ function are facilitated by changes in the levels of circulating factors that act both directly and indirectly on tissue-specific stem cells throughout the body.…”

“…Pusic and Kraig (2014) follow up this study by identifying candidate circulating factors in the form of exosomes which likely underlie this effect. Exosomes released by cells are enriched with specific mRNA, miRNA and proteins that remain bioactive upon uptake by the recipient cell and thus play an important role in intercellular communication (Bobrie et al, 2011).…”

Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes

“…Environmental enrichment for 28 days, which accounts for the spermatogenic cycle of Mus musculus (Oakberg, 1956), could be altering the microRNA content of exosomes secreted by the epididymal epithelial cells which then fuse with the mature sperm in the caudal epididymis (Nixon et al, 2015a(Nixon et al, , 2015b. Environmental enrichment may be altering the dynamics of exosomal release and the microRNA content of these epididysomes, similar to its recently demonstrated impact on peripheral blood mononuclear cells (Pusic and Kraig, 2014;Pusic et al, 2016). Thus, further investigation is required to confirm that environmental enrichment alters the microRNA content of sperm, as well as determine whether the exposure period to an enrichment environment prior to mating modulates the consequential impact on offspring behavior.…”

Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide-labeled exosomes from stem cells: a new method to obtain labeled exosomes

“…12 Exosomes contain lipids, proteins, and nucleic acid (in particular, mRNA, tRNA, miRNA, and noncoding RNA) that can be transferred to cells and regulate their activities. 12,13 Based on the accumulating evidence for the key role of exosomes in neuronal protection, nerve regeneration, remyelination, and synaptic plasticity, [14][15][16][17] several authors support the idea that exosomes can recapitulate the neuroprotective effect of stem cells and suggest their use for a noncell-based therapy of neurodegenerative diseases. 3,[15][16][17] Nevertheless, elucidation of the action mechanism of both ASCs and exosomes requires knowledge of their homing in the recipient body.…”