Carsten Frühbeis

Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication.

Neuronal activity provokes myelinating oligodendrocytes to release exosomes by stimulation of ionotropic glutamate receptors, and that once released, these vesicles are internalized by neurons conveying neuroprotection.

Extracellular vesicles as mediators of neuron-glia communication.

In the nervous system, glia cells maintain homeostasis, synthesize myelin, provide metabolic support, and participate in immune defense. The communication between glia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), such as exosomes and shedding microvesicles, are key players in intercellular signaling. The cells of the nervous system secrete EVs, which potentially carry protein and RNA cargo from one cell to another. After delivery, the cargo has the ability to modify the target cell phenotype. Here, we review the recent advances in understanding the role of EV secretion by astrocytes, microglia, and oligodendrocytes in the central nervous system. Current work has demonstrated that oligodendrocytes transfer exosomes to neurons as a result of neurotransmitter signaling suggesting that these vesicles may mediate glial support of neurons.

Emerging Roles of Exosomes in Neuron–Glia Communication

Brain function depends on coordinated interactions between neurons and glial cells. Recent evidence indicates that these cells release endosome-derived microvesicles termed exosomes, which are 50–100 nm in size and carry specific protein and RNA cargo. Exosomes can interact with neighboring cells raising the concept that exosomes may mediate signaling between brain cells and facilitate the delivery of bioactive molecules. Oligodendrocytes myelinate axons and furthermore maintain axonal integrity by an yet uncharacterized pathway of trophic support. Here, we highlight the role of exosomes in nervous system cell communication with particular focus on exosomes released by oligodendrocytes and their potential implications in axon–glia interaction and myelin disease, such as multiple sclerosis. These secreted vesicles may contribute to eliminate overproduced myelin membrane or to transfer antigens facilitating immune surveillance of the brain. Furthermore, there is emerging evidence that exosomes participate in axon–glia communication.

Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation

Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell–cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen–glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance.

Physical exercise induces rapid release of small extracellular vesicles into the circulation

Cells secrete extracellular vesicles (EVs) by default and in response to diverse stimuli for the purpose of cell communication and tissue homeostasis. EVs are present in all body fluids including peripheral blood, and their appearance correlates with specific physiological and pathological conditions. Here, we show that physical activity is associated with the release of nano-sized EVs into the circulation. Healthy individuals were subjected to an incremental exercise protocol of cycling or running until exhaustion, and EVs were isolated from blood plasma samples taken before, immediately after and 90 min after exercise. Small EVs with the size of 100–130 nm, that carried proteins characteristic of exosomes, were significantly increased immediately after cycling exercise and declined again within 90 min at rest. In response to treadmill running, elevation of small EVs was moderate but appeared more sustained. To delineate EV release kinetics, plasma samples were additionally taken at the end of each increment of the cycling exercise protocol. Release of small EVs into the circulation was initiated in an early phase of exercise, before the individual anaerobic threshold, which is marked by the rise of lactate. Taken together, our study revealed that exercise triggers a rapid release of EVs with the characteristic size of exosomes into the circulation, initiated in the aerobic phase of exercise. We hypothesize that EVs released during physical activity may participate in cell communication during exercise-mediated adaptation processes that involve signalling across tissues and organs.

Oligodendroglial p130Cas Is a Target of Fyn Kinase Involved in Process Formation, Cell Migration and Survival

Oligodendrocytes are the myelinating glial cells of the central nervous system. In the course of brain development, oligodendrocyte precursor cells migrate, scan the environment and differentiate into mature oligodendrocytes with multiple cellular processes which recognize and ensheath neuronal axons. During differentiation, oligodendrocytes undergo dramatic morphological changes requiring cytoskeletal rearrangements which need to be tightly regulated. The non-receptor tyrosine kinase Fyn plays a central role in oligodendrocyte differentiation and myelination. In order to improve our understanding of the role of oligodendroglial Fyn kinase, we have identified Fyn targets in these cells. Purification and mass-spectrometric analysis of tyrosine-phosphorylated proteins in response to overexpressed active Fyn in the oligodendrocyte precursor cell line Oli-neu, yielded the adaptor molecule p130Cas. We analyzed the function of this Fyn target in oligodendroglial cells and observed that reduction of p130Cas levels by siRNA affects process outgrowth, the thickness of cellular processes and migration behavior of Oli-neu cells. Furthermore, long term p130Cas reduction results in decreased cell numbers as a result of increased apoptosis in cultured primary oligodendrocytes. Our data contribute to understanding the molecular events taking place during oligodendrocyte migration and morphological differentiation and have implications for myelin formation.

Lieferung auf Abruf: Exosomen als „Care“-Pakete von Gliazellen für gestresste Neurone

Zusammenfassung Die Kommunikation zwischen Zellen ist eine grundlegende Voraussetzung für reibungslose Abläufe im Nervensystem. Gliazellen besitzen dabei eine Vielzahl von Aufgaben, die in enger Abstimmung mit Neuronen wahrgenommen werden. Forschungen der letzten Jahre zeigen, dass Zellkommunikation auch über den Austausch von extrazellulären Vesikeln stattfindet, die ebenfalls von Gliazellen und Neuronen sezerniert werden. Zu den extrazellulären Vesikeln gehören Exosomen und Mikrovesikel, welche Proteine und Ribonukleinsäuren zu Zielzellen transportieren. Nach erfolgtem Transfer können diese Komponenten dann den Phänotyp der Zielzelle verändern. In diesem Artikel diskutieren wir Eigenschaften und Funktionen von extrazellulären Vesikeln im Allgemeinen und speziell im zentralen Nervensystem. Dort geben myelinisierende Oligodendrozyten in Antwort auf Neurotransmittersig-nale Exosomen ab, die von Neuronen aufgenommen werden und neuroprotektive Eigenschaften besitzen.

Delivery on call: exosomes as “care packages” from glial cells for stressed neurons

Communication between cells is a basic requirement for proper nervous system function. Glial cells execute various functions, operating in close coordination with neurons. Recent research revealed that cell communication is mediated by the exchange of extracellular vesicles, which are also secreted by glial cells and neurons. Extracellular vesicles comprise exosomes and microvesicles, which deliver proteins and ribonucleic acids to target cells. As a result of transfer, the vesicle cargo components can modulate the phenotype of recipient cells. Here, we discuss the characteristics and functions of extracellular vesicles in general and in particular in the central nervous system, where myelinating oligodendrocytes release exosomes in response to neurotransmitter signals, which are internalized by neurons and exhibit neuroprotective functions.