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Review
. 2016 Apr 1;126(4):1198-207.
doi: 10.1172/JCI81134. Epub 2016 Apr 1.

Extracellular vesicles and intercellular communication within the nervous system

Valentina Zappulli, Kristina Pagh Friis, Zachary Fitzpatrick, Casey A Maguire, Xandra O Breakefield
Review

Extracellular vesicles and intercellular communication within the nervous system

Valentina Zappulli et al. J Clin Invest. .

Abstract

Extracellular vesicles (EVs, including exosomes) are implicated in many aspects of nervous system development and function, including regulation of synaptic communication, synaptic strength, and nerve regeneration. They mediate the transfer of packets of information in the form of nonsecreted proteins and DNA/RNA protected within a membrane compartment. EVs are essential for the packaging and transport of many cell-fate proteins during development as well as many neurotoxic misfolded proteins during pathogenesis. This form of communication provides another dimension of cellular crosstalk, with the ability to assemble a "kit" of directional instructions made up of different molecular entities and address it to specific recipient cells. This multidimensional form of communication has special significance in the nervous system. How EVs help to orchestrate the wiring of the brain while allowing for plasticity associated with learning and memory and contribute to regeneration and degeneration are all under investigation. Because they carry specific disease-related RNAs and proteins, practical applications of EVs include potential uses as biomarkers and therapeutics. This Review describes our current understanding of EVs and serves as a springboard for future advances, which may reveal new important mechanisms by which EVs in coordinate brain and body function and dysfunction.

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Figures

Figure 1
Figure 1. EV-mediated intercellular communication between cells in the nervous system.
(i) Astrocyte-derived EVs stimulate dendritic arborization of neurons by transport and release of synapsin I (21); (ii) EVs from microglia increase neuronal synaptic activity, and (iii) neuron-derived EVs activate glial cell functions, such as microglia phagocytosis for clearance of inactive synapses and toxic proteins (44, 148). (iv) EVs from oligodendrocytes enhance stress tolerance of neurons, stimulate anterograde transport of signaling molecules in neurons, and carry proteolipoprotein (PLP), which is important for myelination (9, 45). (v) Immature neural progenitor cells release proteins, such as the L1 adhesion molecule, the glycosylphosphatidyl-inositol–anchored (GPI-anchored) prion protein, and the GluR2/3 subunit of the glutamate receptor, via EVs, which participate in early brain development (7). (vi) Retrotransposons can be transported between cells through the EV compartment. During neurogenesis, the activity of retrotransposons is increased, resulting in a high degree of somatic mosaicism in neuronal genomes (31).
Figure 2
Figure 2. EVs in nervous system physiology and pathology.
(A) The role of EVs in synaptic communication. The addition of GABAA receptor antagonists results in the release of presynaptic EVs that are taken up by postsynaptic cells and modulate synaptic strength and retrograde signaling. They can also activate glial functions, such as microglia phagocytosis for clearance of inactive synapses and release of cytokines and complement. Synaptic vesicles (SV) fuse with the plasma membrane to release neurotransmitters (NT) into the extracellular space, which bind to receptors on postsynaptic neurons, while EVs are released intact into this space by fusion of multivesicular bodies (MVB) with the plasma membrane or budding from the plasma membrane. (B) The role of EVs in axonal regeneration in the peripheral nervous system is mediated by Schwann cells that release EVs containing proteins, miRNA, mRNA, and ribosomes to promote axonal growth. (C) In the pathogenesis of neurodegenerative diseases, (i) EVs can modulate phagocytic clearing of misfolded proteins, such as that described for Aβ in AD. On the other hand, EVs can promote extracellular release, (ii) cell-to-cell spreading, and (iii) accumulation of toxic proteins such as tau, SOD1, TDP-43, and prions, all of which are associated with neuronal degeneration.
Figure 3
Figure 3. Vesicular exchange in the brain tumor microenvironment.
GBM tumors are made up of a heterogeneous group of genetically related cancer cells, shown here as two types of differentiated tumor cells (DTCs) within the same tumor. Tumors also contain glioma stem cells (GSCs), which tend to be resistant to therapy and are thought to rejuvenate differentiated tumor cells after therapy. Tumor cells release at least three types of vesicles — exosomes, microvesicles, and large oncosomes. Normal cells in the brain tumor environment include T cells, microglia, macrophages, and endothelial cells, which also release exosomes and microvesicles. The secretome and EVs of the tumors modulate the phenotype of these normal cells, including promoting an immune-repressive T cell Th2 phenotype, stimulating microglia and macrophages to assume the M2-activated state in support of tumor progression, and inducing endothelial cell–mediated angiogenesis as well as opening up the extracellular matrix (ECM) to facilitate invasion of cancer cells. Vesicles, shown with color coding that matches the cell of origin, are exchanged among all cells in the environment. They all contain a cell-specific cargo of lipids, proteins, and nucleic acids, which are delivered into recipient cells.
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