An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination.
An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination.
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DOI：
10.1038/ncomms11312
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发表时间：
2016-04-26
影响因子：
16.6
通讯作者：
Yong VW
中科院分区：
文献类型：
--
作者：
Keough MB;Rogers JA;Zhang P;Jensen SK;Stephenson EL;Chen T;Hurlbert MG;Lau LW;Rawji KS;Plemel JR;Koch M;Ling CC;Yong VW
再髓鞘形成是损伤后通过分化少突胶质前体细胞(OPC)的过程促进新髓鞘的产生。虽然这种修复现象发生在多发性硬化症患者的皮损中，但许多皮损未能完全再生髓鞘。已经确定了许多因素导致再髓鞘形成失败，包括上调的硫酸软骨素蛋白多糖(CSPGs)，它构成了星形胶质瘢痕的一部分。我们发现，在体外，OPC显著减少了CSPGs存在时的突起生长，并且包括最近报道的一些OPC分化药物的药物库未能挽救CSPGs上的这种抑制表型。我们介绍了一种新的CSPG合成抑制剂，以降低CSPG的含量，并在体外发现OPC的救助性突起，并加速小鼠局灶性脱髓鞘后的重髓鞘形成。防止CSPG沉积到病变微环境中可能是促进多发性硬化症和其他神经疾病修复的有用策略。星形胶质细胞分泌的硫酸软骨素蛋白多糖(CSPGs)可抑制OPC分化和再髓鞘形成。在这里，作者发现了一种新的CSPG合成抑制剂，并发现它可以在体外挽救OPC的分化，并加速小鼠局灶性脱髓鞘后的重新髓鞘形成。
Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders. Chondroitin sulfate proteoglycans (CSPGs) secreted by astrocytes are known to inhibit OPC differentiation and remyelination. Here, the authors identify a novel CSPG synthesis inhibitor and find it can rescue OPC differentiation in vitro and accelerate remyelination in mice following focal demyelination.