Rodriguez Enrique Garea, Wegner Christiane, Kreutzfeldt Mario, Neid Katharina, Thal Dietmar R, Jürgens Tanja, Brück Wolfgang, Stadelmann Christine, Merkler Doron
Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37099, Göttingen, Germany.
Acta Neuropathol. 2014 Aug;128(2):231-46. doi: 10.1007/s00401-014-1260-8. Epub 2014 Feb 25.
Cerebral cortex shows a high endogenous propensity for remyelination. Yet, widespread subpial cortical demyelination (SCD) is a common feature in progressive multiple sclerosis (MS) and can already be found in early MS. In the present study, we compared oligodendroglial loss in SCD in early and chronic MS. Furthermore, we addressed in an experimental model whether repeated episodes of inflammatory SCD could alter oligodendroglial repopulation and subsequently lead to persistently demyelinated cortical lesions. NogoA(+) mature oligodendrocytes and Olig2(+) oligodendrocyte precursor cells were examined in SCD in patients with early and chronic MS, normal-appearing MS cortex, and control cortex as well as in the rat model of repeated targeted cortical experimental autoimmune encephalomyelitis (EAE). NogoA(+) and Olig2(+) cells were significantly reduced in SCD in patients with chronic, but not early MS. Repeated induction of SCD in rats resulted only in a transient loss of NogoA(+), but not Olig2(+) cells during the demyelination phase. This phase was followed by complete oligodendroglial repopulation and remyelination, even after four episodes of demyelination. Our data indicate efficient oligodendroglial repopulation in subpial cortical lesions in rats after repeated SCD that was similar to early, but not chronic MS cases. Accordingly, four cycles of experimental de- and remyelination were not sufficient to induce sustained remyelination failure as found in chronic cortical MS lesions. This suggests that alternative mechanisms contribute to oligodendrocyte depletion in chronic cortical demyelination in MS.
大脑皮层显示出较高的内源性髓鞘再生倾向。然而,广泛的软膜下皮质脱髓鞘(SCD)是进展性多发性硬化症(MS)的一个常见特征,在早期MS中就已出现。在本研究中,我们比较了早期和慢性MS中SCD区域少突胶质细胞的损失情况。此外,我们在一个实验模型中探讨了炎症性SCD的反复发作是否会改变少突胶质细胞的再填充,并随后导致持续脱髓鞘的皮质病变。我们检测了早期和慢性MS患者、外观正常的MS皮质以及对照皮质的SCD区域中NogoA(+)成熟少突胶质细胞和Olig2(+)少突胶质前体细胞,以及在反复靶向皮质实验性自身免疫性脑脊髓炎(EAE)大鼠模型中的情况。慢性MS患者的SCD区域中NogoA(+)和Olig2(+)细胞显著减少,但早期MS患者中没有。在大鼠中反复诱导SCD仅导致脱髓鞘阶段NogoA(+)细胞短暂丢失,而Olig2(+)细胞没有。即使在经历四次脱髓鞘发作后,这个阶段之后仍会出现少突胶质细胞的完全再填充和髓鞘再生。我们的数据表明,在大鼠反复发生SCD后,软膜下皮质病变中的少突胶质细胞能够有效再填充,这与早期MS病例相似,但与慢性MS病例不同。因此,四个周期的实验性脱髓鞘和髓鞘再生不足以诱导出慢性皮质MS病变中所见的持续性髓鞘再生失败。这表明在MS慢性皮质脱髓鞘中,少突胶质细胞耗竭存在其他机制。