Cheng Xiaoxin, Wang Yaping, He Qian, Qiu Mengsheng, Whittemore Scott R, Cao Qilin
Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, MDR 616, 511 South Floyd Street, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Stem Cells. 2007 Dec;25(12):3204-14. doi: 10.1634/stemcells.2007-0284. Epub 2007 Sep 13.
Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understanding the molecular mechanisms that regulate the differentiation of adult OPCs could lead to new therapeutic strategies to treat these disorders. In this study, we established a stable culture of adult spinal cord OPCs and developed a reliable in vitro protocol to induce their sequential differentiation. Adult OPCs expressed bone morphogenetic protein (BMP) type Ia, Ib, and II receptor subunits, which are required for BMP signal transduction. BMP2 and 4 promoted dose-dependent astrocyte differentiation of adult OPCs with concurrent suppression of OL differentiation. Treatment of OPCs with BMP2 and 4 increased ID4 expression and decreased the expression of olig1 and olig2. Overexpression of olig1 or olig2 blocked the astrocyte differentiation of adult OPCs induced by BMP2 and 4. Furthermore, overexpression of both olig1 and olig2, but not olig1 or olig2 alone, rescued OL differentiation from inhibition by BMP2 and 4. Our results demonstrated that downregulation of olig1 and olig2 is an important mechanism by which BMP2 and 4 inhibit OL differentiation of adult OPCs. These data suggest that blocking BMP signaling combined with olig1/2 overexpression could be a useful therapeutic strategy to enhance endogenous remyelination and facilitate functional recovery in CNS demyelinated disorders. Disclosure of potential conflicts of interest is found at the end of this article.
促进髓鞘再生是治疗脱髓鞘性神经疾病的重要治疗策略。成年少突胶质前体细胞（OPCs）通常静止地存在于成年中枢神经系统（CNS）中，在脱髓鞘损伤后会被激活并增殖。然而，由于成年OPCs在脱髓鞘的CNS中未能成熟为形成髓鞘的少突胶质细胞（OLs），内源性髓鞘再生的程度有限。了解调节成年OPCs分化的分子机制可能会带来治疗这些疾病的新策略。在本研究中，我们建立了成年脊髓OPCs的稳定培养体系，并开发了一种可靠的体外方案来诱导其顺序分化。成年OPCs表达骨形态发生蛋白（BMP）Ia、Ib和II型受体亚基，这些是BMP信号转导所必需的。BMP2和4促进成年OPCs剂量依赖性的星形胶质细胞分化，同时抑制OL分化。用BMP2和4处理OPCs会增加ID4表达并降低olig1和olig2的表达。olig1或olig2的过表达会阻断BMP2和4诱导的成年OPCs的星形胶质细胞分化。此外，olig1和olig2两者的过表达，而不是单独的olig1或olig2，可使OL分化从BMP2和4的抑制中恢复。我们的结果表明，olig1和olig2的下调是BMP2和4抑制成年OPCs的OL分化的重要机制。这些数据表明，阻断BMP信号传导并结合olig1/2过表达可能是增强内源性髓鞘再生并促进CNS脱髓鞘疾病功能恢复的有用治疗策略。潜在利益冲突的披露见本文末尾。
