Abstract
Oligodendrocytes form myelin membranes and thereby secure the insulation of axons and the rapid conduction of action potentials. Diseases such as multiple sclerosis highlight the importance of this glial cell population for brain function. In the adult brain, efficient remyelination following the damage to oligodendrocytes is compromised. Myelination is characterized by proliferation, migration, and proper integration of oligodendrocyte precursor cells (OPCs). These processes are among others controlled by proteins of the extracellular matrix (ECM). As a prominent representative ECM molecule, tenascin-C (Tnc) exerts an inhibitory effect on the migration and differentiation of OPCs. The structurally similar paralogue tenascin-R (Tnr) is known to promote the differentiation of oligodendrocytes. The model of lysolecithin-induced demyelination of cerebellar slice cultures represents an important tool for the analysis of the remyelination process. Ex vivo cerebellar explant cultures of Tnc −/− and Tnr −/− mouse lines displayed enhanced remyelination by forming thicker myelin membranes upon exposure to lysolecithin. The inhibitory effect of tenascins on remyelination could be confirmed when demyelinated wildtype control cultures were exposed to purified Tnc or Tnr protein. In that approach, the remyelination efficiency decreased in a dose-dependent manner with increasing concentrations of ECM molecules added. In order to examine potential roles in a complex in vivo environment, we successfully established cuprizone-based acute demyelination to analyze the remyelination behavior after cuprizone withdrawal in SV129, Tnc −/− , and Tnr −/− mice. In addition, we documented by immunohistochemistry in the cuprizone model the expression of chondroitin sulfate proteoglycans that are inhibitory for the differentiation of OPCs. In conclusion, inhibitory properties of Tnc and Tnr for myelin membrane formation could be demonstrated by using an ex vivo approach.
Highlights
Neurons, astrocytes, oligodendrocytes, and microglia form part of the four determining cell types of the central nervous system (CNS), whose interactions are necessary for memory formation (Hertz and Chen, 2016)
Immunohistochemical staining with NF200 and Myelin basic protein (MBP) was performed in four conditions, namely, myelinated (M), demyelinated (DM), remyelinated (RM), and control (C) (Figures 2–5)
We investigated the influence of the glycoproteins Tnc and especially Tnr on the differentiation and remyelination efficiency of oligodendrocytes
Summary
Astrocytes, oligodendrocytes, and microglia form part of the four determining cell types of the central nervous system (CNS), whose interactions are necessary for memory formation (Hertz and Chen, 2016). In demyelinated MS plaques, which are characterized by demyelination of axons, an upregulation of Tnc may mediate inhibitory influences on oligodendrocytes (Zhao et al, 2009) Along these lines, when experimental allergic encephalomyelitis (EAE) was elicited in Tnc−/− mice, the disease course was less severe than that in the wildtype. Tnr promotes cell adhesion and cell differentiation of oligodendrocytes and blocks migration of OPCs (Pesheva et al, 1997) Both tenascins exert an inhibitory influence on formation of myelin membranes. We wanted to analyze the influence of Tnr on remyelination efficiency and on differentiation of oligodendrocytes Within both demyelination models, Tnc−/− and Tnr−/− mice are used for the first time. We show that both demyelination models can be performed with Tnc−/− and Tnr−/− mice Both glycoproteins Tnc and Tnr revealed an inhibitory influence on remyelination efficiency of oligodendrocytes in ex vivo explants. The known inhibitory effect of chondroitin sulfate on differentiation of OPCs (Karus et al, 2016; Keough et al, 2016) proved consistent with the expression pattern observed in this study
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