Molecular pathology of Multiple Sclerosis lesions reveals a heterogeneous expression pattern of genes involved in oligodendrogliogenesis

• Published in: Experimental neurology 2018-07, Vol.305, p.76-88
• Main Authors: Zeis, T., Howell, O.W., Reynolds, R., Schaeren-Wiemers, N.
• Format: Article
• Language: English
• Subjects: Adult; Female; Gene Expression; Gene expression analysis; Humans; Male; Middle Aged; Molecular pathology; Multiple Sclerosis; Multiple Sclerosis - epidemiology; Multiple Sclerosis - genetics; Multiple Sclerosis - pathology; Multiple Sclerosis lesions; Oligodendroglia - pathology; Oligodendroglia - physiology; Oligodendrogliogenesis; STAT6 pathway; Tissue Banks - trends; United Kingdom - epidemiology
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2018.03.012

Little is known about the decisive molecular factors that regulate lesion remyelination in Multiple Sclerosis. To identify such factors, we performed a differential gene expression analysis of normal appearing white matter (NAWM), active, remyelinating, and inactive demyelinated lesions. As expected, many genes involved in inflammatory processes were detected to be differentially regulated between these tissue types. Among them, we found an increased expression of members of the STAT6 pathway such as STAT6, IL4 and IL4R in active, remyelinated and inactive demyelinated lesions. This suggests that a protective, anti-inflammatory reaction, as already reported to be present in MS NAWM, is further enhanced in lesion tissues. Focusing on genes influencing oligodendrogliogenesis, we found a decreased expression of NKX2-2 in active, remyelinated and inactive demyelinated lesions, whereas SOX10 was downregulated in inactive demyelinated lesions, when compared to NAWM. Simultaneously, CXCL12 (SDF1) expression was strongly increased in active, remyelinated and inactive demyelinated lesions, but increased expression of the IGF1 and IGF2 genes was found in inactive demyelinated lesions. This demonstrates that, in principle, expression of genes promoting oligodendrogliogenesis occurs in MS lesion tissue - even in inactive demyelinated lesions. In contrast, oligodendrogenesis inhibiting genes such as JAG1 were also expressed at higher levels in inactive demyelinated lesions. Both, oligodendrogliogenesis promoting as well as inhibiting genes are expressed in all lesion tissues. However, no clear promoting or inhibiting expression pattern could be detected in any of the different types of lesioned tissues. This might reflect the heterogeneity of lesion development in MS patients, both in terms of mechanisms and temporal differences. [Display omitted] •Lesion tissues express both, oligodendrogliogenesis promoting and inhibiting genes.•Gene expression patterns vary significantly in single lesion tissue types.•Gene expression heterogeneity might be causative for non-uniform remyelination.