Bone morphogenetic protein signaling and olig1/2 interact to regulate the differentiation and maturation of adult oligodendrocyte precursor cells
Bone morphogenetic protein signaling and olig1/2 interact to regulate the differentiation and maturation of adult oligodendrocyte precursor cells
复制标题
DOI：
10.1634/stemcells.2007-0284
复制
发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Cao, Qilin
中科院分区：
文献类型：
--
作者：
Cheng, Xiaoxin;Wang, Yaping;Cao, Qilin
促进髓鞘再生是治疗脱髓鞘性神经系统疾病的重要治疗策略。成体少突胶质细胞前体细胞（OPCs）通常静止地存在于成体中枢神经系统（CNS）中，在脱髓鞘病变后变得活化和增殖。然而，内源性髓鞘再生的程度是有限的，因为成年OPCs的失败，以成熟为髓鞘少突胶质细胞（OLs）在脱髓鞘的中枢神经系统。了解调节成人OPCs分化的分子机制可能会导致治疗这些疾病的新的治疗策略。在这项研究中，我们建立了一个稳定的成人脊髓OPCs的培养，并开发了一个可靠的体外方案，以诱导其顺序分化。成年OPCs表达骨形态发生蛋白（BMP）Ia、Ib和II型受体亚单位，这是BMP信号转导所必需的。BMP 2和4促进成人OPCs的剂量依赖性星形胶质细胞分化，同时抑制OL分化。用BMP 2和4处理OPCs可增加ID 4的表达，降低olig 1和olig 2的表达。olig 1或olig 2的过表达可阻断BMP 2和4诱导的成体OPCs向星形胶质细胞分化。此外，olig 1和olig 2的过表达，但不是olig 1或olig 2单独，拯救了骨形态发生蛋白2和4抑制的OL分化。我们的结果表明，olig 1和olig 2的下调是BMP 2和4抑制成人OPCs OL分化的重要机制。这些数据表明，阻断BMP信号传导结合olig 1/2过表达可能是一种有用的治疗策略，以增强内源性髓鞘再生，促进CNS脱髓鞘疾病的功能恢复。
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.