Neurobiology, Department of Biomedicine, University Hospital Basel, University Basel, Zentrum für Lehre und Forschung, Basel, Switzerland.
Institute of Life Sciences, Swansea University Medical School, Swansea SA2 8PP, UK.
Exp Neurol. 2018 Jul;305:76-88. doi: 10.1016/j.expneurol.2018.03.012. Epub 2018 Mar 27.
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.
关于调控多发性硬化症病灶内髓鞘再形成的关键分子因素知之甚少。为了鉴定这些因素，我们对正常表现的白质（NAWM）、活动的、髓鞘再形成的和失活的脱髓鞘病灶进行了差异基因表达分析。正如预期的那样，在这些组织类型之间检测到许多参与炎症过程的基因存在差异调控。其中，我们发现活跃的、髓鞘再形成的和失活的脱髓鞘病灶中 STAT6 通路成员如 STAT6、IL4 和 IL4R 的表达增加。这表明，正如已经在 MS NAWM 中报道的那样，一种保护性的抗炎反应在病灶组织中进一步增强。聚焦于影响少突胶质细胞发生的基因，我们发现活跃的、髓鞘再形成的和失活的脱髓鞘病灶中 NKX2-2 的表达减少，而 SOX10 在失活的脱髓鞘病灶中表达下调，与 NAWM 相比。同时，CXCL12（SDF1）的表达在活跃的、髓鞘再形成的和失活的脱髓鞘病灶中强烈增加，但 IGF1 和 IGF2 基因的表达增加仅在失活的脱髓鞘病灶中发现。这表明，原则上，促进少突胶质细胞发生的基因在 MS 病灶组织中表达 - 即使在失活的脱髓鞘病灶中也是如此。相比之下，少突胶质细胞发生抑制基因如 JAG1 在失活的脱髓鞘病灶中也表达较高。促进少突胶质细胞发生和抑制基因都在所有病灶组织中表达。然而，在任何一种不同类型的病灶组织中都没有检测到明确的促进或抑制表达模式。这可能反映了 MS 患者病灶发展的异质性，无论是在机制上还是在时间上都存在差异。
