Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models.
Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models.
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DOI：
10.1007/s00401-013-1112-y
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发表时间：
2013-06
影响因子：
12.7
通讯作者：
Williams A
中科院分区：
文献类型：
--
作者：
Boyd A;Zhang H;Williams A
多发性硬化（MS）病变髓鞘再生失败导致神经退行性变，与患者的慢性残疾相关。目前，还没有可用的治疗方法来减少神经变性，但一种治疗方法来填补这一未满足的需求是促进髓鞘再生。由于许多脱髓鞘的MS病变含有丰富的少突胶质前体细胞（OPC），但没有成熟的髓鞘少突胶质细胞，以前的研究集中在促进OPC成熟。然而，一些MS病变含有少量OPC，因此，髓鞘再生失败也可能继发于OPC募集失败。在这里，在一系列MS样本中，我们确定了多少病变含有少量OPC，并将其与病理亚型和趋化分子Semaphorin（Sema）3A和3F的表达相关联。37%的MS病变含有低数量的OPC，并且这些主要是慢性活动性病变，其中细胞表达Sema 3A（化学排斥剂）。为了检验脱髓鞘病变中差异性Sema 3表达改变OPC募集和随后髓鞘再生效率的假设，我们使用了局灶性脱髓鞘毒性小鼠模型。向脱髓鞘病变中添加重组（r）Sema 3A（化学排斥剂）减少了OPC募集和髓鞘再生，而添加rSema 3F（化学引诱剂）或使用Sema 3A表达减少的转基因小鼠增加了OPC募集和髓鞘再生。我们的结论是，一些MS病变未能恢复髓鞘继发于减少OPC招聘，和趋化分子参与的机制，提供了一组新的药物靶点，以改善髓鞘再生，在Sema 3A受体neuropilin-1的特定目标。本文的在线版本（doi：10.1007/s 00401 -013-1112-y）包含补充材料，可供授权用户使用。
Failure of remyelination of multiple sclerosis (MS) lesions contributes to neurodegeneration that correlates with chronic disability in patients. Currently, there are no available treatments to reduce neurodegeneration, but one therapeutic approach to fill this unmet need is to promote remyelination. As many demyelinated MS lesions contain plentiful oligodendrocyte precursor cells (OPCs), but no mature myelinating oligodendrocytes, research has previously concentrated on promoting OPC maturation. However, some MS lesions contain few OPCs, and therefore, remyelination failure may also be secondary to OPC recruitment failure. Here, in a series of MS samples, we determined how many lesions contained few OPCs, and correlated this to pathological subtype and expression of the chemotactic molecules Semaphorin (Sema) 3A and 3F. 37 % of MS lesions contained low numbers of OPCs, and these were mostly chronic active lesions, in which cells expressed Sema3A (chemorepellent). To test the hypothesis that differential Sema3 expression in demyelinated lesions alters OPC recruitment and the efficiency of subsequent remyelination, we used a focal myelinotoxic mouse model of demyelination. Adding recombinant (r)Sema3A (chemorepellent) to demyelinated lesions reduced OPC recruitment and remyelination, whereas the addition of rSema3F (chemoattractant), or use of transgenic mice with reduced Sema3A expression increased OPC recruitment and remyelination. We conclude that some MS lesions fail to remyelinate secondary to reduced OPC recruitment, and that chemotactic molecules are involved in the mechanism, providing a new group of drug targets to improve remyelination, with a specific target in the Sema3A receptor neuropilin-1. The online version of this article (doi:10.1007/s00401-013-1112-y) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Fritzsching B;Haas J;König F;Kunz P;Fritzsching E;Pöschl J;Krammer PH;Brück W;Suri-Payer E;Wildemann B
通讯作者：
Wildemann B
影响因子：
--
作者：
Lee, MA;Blamire, AM;Matthews, PM
通讯作者：
Matthews, PM
影响因子：
3.5
作者：
Eickholt, BJ;Morrow, R;Doherty, P
通讯作者：
Doherty, P
影响因子：
6.2
作者：
Lee, KK;De Repentigny, Y;Kothary, R
通讯作者：
Kothary, R
影响因子：
158.5
作者：
Chang, A;Tourtellotte, WW;Trapp, BD
通讯作者：
Trapp, BD