from Neuropsychopharmacology Reviews by Eva-Maria Krämer-Albers and Wen Ping Kuo-Elsne
Brain homeostasis requires extensive signaling and information exchange between all types of neural cells, including neurons and glia. Recent studies indicated a pivotal role of extracellular vesicles (EVs) in communication between neural cells and furthermore, in the conversation between neural cells and the periphery. EVs comprise a group of varied secreted vesicles (plasma membrane-derived microvesicles and endosome-derived exosomes), which recently came into focus regarding their ability to shuttle biomolecules including RNA between cells and their potential to phenotypically modulate target cells. Apparently, all types of neural cells release EVs, which have been implicated in several physiological and pathological processes such as neuromodulation, synaptic plasticity, neuron-glia-interaction, and the spreading of neuropathological agents. Notably, EVs with the characteristics of exosomes seem to have a remarkable role in neuroprotection and neuroregeneration. Oligodendrocytes release exosomes in response to neurotransmitter signaling, that transfer cargo to neurons and enhance the tolerance of recipient neurons toward different types of cell stress (Frühbeis et al, 2013). These exosomes convey multilevel information by transferring stress-protective enzymes (Hsp70, SOD1, and catalase), activation of pro-survival signaling pathways and modulation of gene expression. In similar fashion, EVs secreted by Schwann-cells are internalized by neurons in the peripheral nervous system and promote axonal regeneration after injury by increasing axon elongation (Lopez-Verrilli et al, 2013). Thus, EVs transferred from myelinating glia cells to neurons convey neuroprotective and pro-regenerative messages and provide local support to facilitate axonal maintenance, homeostasis, and axonal growth. It is therefore conceivable that application of glial exosomes may offer a therapeutic opportunity to benefit neurons and prevent axonal death in the course of demyelinating diseases or other sorts of neural injury.
Moreover, there is compelling evidence that EVs released by cells in the periphery can enter the CNS and accomplish pro-neural activity. EVs derived from hematopoietic cells are able to pass the blood–brain barrier and deliver genetic information in form of mRNA and miRNAs to CNS neurons, in particular under inflammatory conditions (Ridder et al, 2014). It has been suggested that IFNγ-stimulated dendritic cells release EVs that promote CNS myelination and might be applied for remyelination therapies (Pusic et al, 2014). Furthermore, recent developments in the field of cell therapy strongly suggest that the systemic regenerative potential of stem cells observed in several neurological disorders is not revealed by cell engraftment, but largely due to paracrine signals delivered by EVs entering the CNS or modulating inflammatory responses. In a rat model of ischemia, intravenous administration of EVs originating from mesenchymal stromal cells improved functional recovery, which was related to enhanced neurite remodeling, neurogenesis, and neovascularization due to EV-mediated transfer of miRNAs to neural target cells (Xin et al, 2013). Neural stem cells (NSCs), which facilitate functional recovery upon systemic application in a number of neural diseases, release EVs after exposure to pro-inflammatory cytokines that are considered to mediate immunomodulation in the host environment (Cossetti et al, 2014).
In conclusion, EVs derived from cells within the nervous system as well as EVs entering the CNS from the periphery emerge as potent conveyors of complex messages in benefit of neural health. Future studies will be needed to uncover their full potential as therapeutic agents and to unravel their mode of action.