Extracellular Vesicles in neural cell interaction and CNS homeostasis

Abstract

Central nervous system (CNS) homeostasis critically depends on the interaction between neurons and glia cells. Extracellular vesicles (EVs) recently emerged as versatile messengers in CNS cell communication. EVs are released by neurons and glia in activity-dependent manner and address multiple target cells within and outside the nervous system. Here, we summarize the recent advances in understanding the physiological roles of EVs in the nervous system and their ability to deliver signals across the CNS barriers. In addition to the disposal of cellular components via EVs and clearance by phagocytic cells, EVs are involved in plasticity-associated processes, mediate trophic support and neuroprotection, promote axonal maintenance, and modulate neuroinflammation. While individual functional components of the EV cargo are becoming progressively identified, the role of neural EVs as compound multimodal signaling entities remains to be elucidated. Novel transgenic models and imaging technologies allow EV tracking in vivo and provide further insight into EV targeting and their mode of action. Overall, EVs represent key players in the maintenance of CNS homeostasis essential for the lifelong performance of neural networks and thus provide a wide spectrum of biomedical applications.

Keywords: axonal maintenance; blood–brain barrier; exosomes; in vivo imaging; microvesicles; neuroinflammation; neuron–glia interaction; synaptic plasticity.

FIGURE 1

CNS EVs and their target cells. (A) Neurons and the different types of glial cells stimulated by neurotransmitter signaling or cytokines release EVs, which are committed to deliver their cargo to other cells of the CNS. Neuronal (B) and glial EVs (C–F) mediate a range of functions that regulate local adaptive processes and CNS homeostasis

FIGURE 2

Brain–periphery interaction mediated by EVs. (A) EVs derived from peripheral cells enter the brain by crossing its different barriers. EVs produced by degenerating neural cells reach the circulation, utilized for liquid biopsy. Dashed lines indicate that the mechanism of transfer across the barrier is unknown. (B) EVs interacting with BMECs at the blood–brain barrier and their functions. (C) Blood–CSF barrier and effects of CPE‐derived EVs on neural cells. CNS, central nervous system; BMEC, brain microvascular endothelial cell; BBB, blood–brain barrier; OPC, oligodendroglial progenitor cell; MSC, mesenchymal stem cell; CPE, choroid plexus epithelial cells; CSF, cerebrospinal fluid