Foote A K, Blakemore W F
Department of Veterinary Medicine, University of Cambridge, UK.
Brain. 2005 Mar;128(Pt 3):528-39. doi: 10.1093/brain/awh417. Epub 2005 Feb 7.
A major challenge in multiple sclerosis research is to understand the cause or causes of remyelination failure and to devise ways of ameliorating its consequences. This requires appropriate experimental models. Although there are many models of acute demyelination, at present there are few suitable models of chronic demyelination. The taiep rat is a myelin mutant that shows progressive myelin loss and, by 1 year of age, its CNS tissue has many features of chronic areas of demyelination in multiple sclerosis: chronically demyelinated axons present in an astrocytic environment in the absence of acute inflammation. Using the taiep rat and a combination of X-irradiation and cell transplantation, it has been possible to address a number of questions concerning remyelination failure in chronic multiple sclerosis lesions, such as whether chronically demyelinated axons have undergone changes that render them refractory to remyelination and why remyelination is absent when oligodendrocyte progenitor cells (OPCs) are present. Our experiments show that (i) transplanted OPCs will not populate OPC-containing areas of chronic demyelination; (ii) myelination competent OPCs can repopulate OPC-depleted chronically demyelinated astrocytosed tissue, but this repopulation does not result in remyelination--closely resembling the situation found in some multiple sclerosis plaques; and (iii) the induction of acute inflammation in this non-remyelinating situation results in remyelination. Thus, we can conclude that axonal changes induced by chronic demyelination are unlikely to contribute to remyelination failure in multiple sclerosis. Rather, remyelination fails either because OPCs fail to repopulate areas of demyelination or because if OPCs are present they are unable to generate remyelinating oligodendrocytes owing to the presence of inhibitory factors and/or a lack of the stimuli required to activate these cells to generate remyelinating oligodendrocytes. This non-remyelinating situation can be transformed to a remyelinating one by the induction of acute inflammation.
多发性硬化症研究中的一个主要挑战是了解髓鞘再生失败的原因，并设计方法改善其后果。这需要合适的实验模型。虽然有许多急性脱髓鞘模型，但目前适合慢性脱髓鞘的模型很少。泰耶普大鼠是一种髓鞘突变体，表现出进行性髓鞘丢失，到1岁时，其中枢神经系统组织具有多发性硬化症慢性脱髓鞘区域的许多特征：在没有急性炎症的情况下，慢性脱髓鞘轴突存在于星形细胞环境中。利用泰耶普大鼠以及X射线照射和细胞移植的组合，已经能够解决一些关于慢性多发性硬化症病变中髓鞘再生失败的问题，例如慢性脱髓鞘轴突是否发生了使其难以进行髓鞘再生的变化，以及当少突胶质前体细胞（OPC）存在时为何没有髓鞘再生。我们的实验表明：（i）移植的OPC不会在含有OPC的慢性脱髓鞘区域聚集；（ii）具有髓鞘形成能力的OPC可以重新填充OPC缺失的慢性脱髓鞘星形细胞化组织，但这种重新填充不会导致髓鞘再生——这与在一些多发性硬化症斑块中发现的情况非常相似；（iii）在这种无髓鞘再生的情况下诱导急性炎症会导致髓鞘再生。因此，我们可以得出结论，慢性脱髓鞘诱导的轴突变化不太可能导致多发性硬化症中的髓鞘再生失败。相反，髓鞘再生失败要么是因为OPC未能重新填充脱髓鞘区域，要么是因为如果OPC存在，由于抑制因子的存在和/或缺乏激活这些细胞以产生髓鞘再生少突胶质细胞所需的刺激，它们无法产生髓鞘再生的少突胶质细胞。通过诱导急性炎症，这种无髓鞘再生的情况可以转变为有髓鞘再生的情况。
