Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival
Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival
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DOI：
10.1007/s00018-013-1340-2
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发表时间：
2013-09-01
影响因子：
8
通讯作者：
de Castro, F.
中科院分区：
文献类型：
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作者：
Medina-Rodriguez, E. M.;Arenzana, F. J.;de Castro, F.
在中枢神经系统 (CNS) 的发育过程中，少突胶质细胞前体 (OPC) 在神经管内的特定位点产生，然后迁移到整个中枢神经系统，并在那里分化为形成髓磷脂的少突胶质细胞。多发性硬化症 (MS) 等脱髓鞘疾病的特征是这些细胞的死亡。中枢神经系统对脱髓鞘反应并通过促进自发髓鞘再生来进行反应，这是由内源性 OPC 介导的效应，这种细胞约占成人大脑细胞的 5-7%。许多因素影响少突胶质细胞生成和少突胶质细胞分化，包括形态发生素、生长因子、趋化分子、细胞外基质蛋白和细胞内 cAMP 水平。在这里，我们发现在发育期间和成年早期，小鼠大脑皮层中的 OPC 含有代谢 cAMP 的磷酸二酯酶 7 (PDE7)。我们研究了不同 PDE7 抑制剂（众所周知的 BRL-50481 和两种新抑制剂 TC3.6 和 VP1.15）对 OPC 增殖、存活和分化的影响。虽然没有一种 PDE7 抑制剂分析了 OPC 增殖的改变，但 TC3.6 和 VP1.15 增强了 OPC 的存活和分化，而 ERK 细胞内信号传导在其中发挥了关键作用。在从成人大脑中分离出的 OPC 中也观察到了 PDE7 表达，并且用两种新的 PDE7 抑制剂治疗加速了这些 OPC 分化为更成熟的少突胶质细胞表型。这些发现揭示了 PDE7 在大脑发育和成年期间调节 OPC 存活和分化的新作用，它们可能会进一步加深我们对髓鞘形成的理解，并促进治疗多发性硬化症的髓鞘再生策略的开发。
During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5-7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.