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

TLDR

Oligodendrocytes form CNS myelin by wrapping axons, and major myelin proteins such as PLP accumulate in late endosomal multivesicular bodies that fuse with the plasma membrane to release exosomes into the extracellular space. The study demonstrates that cultured oligodendrocytes secrete exosomes enriched in PLP and CNP. These exosomes have a characteristic density of 1.10–1.14 g/mL in sucrose gradients. Calcium ionophore ionomycin boosts PLP‑containing exosome release, and proteomic profiling reveals that oligodendroglial exosomes also carry MBP, MOG, CNP and stress‑protective proteins, suggesting a role in balanced myelin production and axonal trophic support.

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.