Oligodendrocytes secrete exosomes containing major myelin and stress‐protective proteins: Trophic support for axons?

Abstract

Oligodendrocytes synthesize the CNS myelin sheath by enwrapping axonal segments with elongations of their plasma membrane. Spatial and temporal control of membrane traffic is a prerequisite for proper myelin formation. The major myelin proteolipid protein (PLP) accumulates in late endosomal storage compartments and multivesicular bodies (MVBs). Fusion of MVBs with the plasma membrane results in the release of the intralumenal vesicles, termed exosomes, into the extracellular space. Here, we show that cultured oligodendrocytes secrete exosomes carrying major amounts of PLP and 2'3'-cyclic-nucleotide-phosphodiesterase (CNP). These exosomes migrated at the characteristic density of 1.10-1.14 g/mL in sucrose density gradients. Treatment of primary oligodendrocytes with the calcium-ionophore ionomycin markedly increased the release of PLP-containing exosomes, indicating that oligodendroglial exosome secretion is regulated by cytosolic calcium levels. A proteomic analysis of the exosomal fraction isolated by sucrose density centrifugation revealed in addition to PLP and CNP, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) as constituents of oligodendroglial exosomes, together with a striking group of proteins with proposed functions in the relief of cell stress. Oligodendroglial exosome secretion may contribute to balanced production of myelin proteins and lipids, but in addition exosomes may embody a signaling moiety involved in glia-mediated trophic support to axons.

Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

“…These results may imply a novel immunosuppressive action of the drug, that is, FTY720 treatment causes inhibition of S1P signalling on MVEs, which blocks exosomal MVE maturation, that may affect early steps of immunization, for example, an exosome-related phenomenon such as antigen presentation by dendritic cells. Indeed, oligodendrocytes secrete relatively large amounts of exosomes enriched in myelin proteolipid protein in the central nervous system, a candidate of autoantigen in multiple sclerosis 30,61 . As for the mechanism of depletion of S1P 1 receptors from MVEs, it has recently been shown that S1P 1 receptors were accumulated to Golgi/trans-Golgi network and scarcely found in endosomes for several hours after treatment of cells with FTY720 (ref.…”

Extracellular-vesicle type of volume transmission and tunnelling-nanotube type of wiring transmission add a new dimension to brain neuro-glial networks

“…In addition, other cells in the CNS such as astrocytes [68,69], microglial cells [70] and oligodendrocytes [71] release EMVs (table 3). Astrocytes can release EMVs by an ATPinduced stimulation of P2X7 receptors followed by an action of acid sphingomyelinase [72].…”

“…The oligodendrocyte exosomes contain myelin proteins such as PLP and CNP, glycolytic enzymes, stress protective proteins, mRNA and miRNA [71] (table 3). Axonally released glutamate activates exosome release from oligodendroglia mediated mainly by glial NMDA receptors [77].…”

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

“…Confocal microscopy studies suggested co-localization of PDGFR␣ with sulfatides in ASA ϩ/ϩ and to a lesser extent in ASA Ϫ/Ϫ NPs (data not shown). There is evidence that sulfatides are components of exosomal membranes (82). However, exosomes isolated from NPs appeared to contain little if any sulfatide (data not shown).…”