Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Neurobiol Dis. 2012 Jan;45(1):196-205. doi: 10.1016/j.nbd.2011.08.004. Epub 2011 Aug 10.
The adult mammalian brain contains multiple populations of endogenous progenitor cell types. However, following CNS trauma or disease, the regenerative capacity of progenitor populations is typically insufficient and may actually be limited by non-permissive or inhibitory signals in the damaged parenchyma. Remyelination is the most effective and simplest regenerative process in the adult CNS yet is still insufficient following repeated or chronic demyelination. Our previous in vitro studies demonstrated that fibroblast growth factor receptor 1 (FGFR1) signaling inhibited oligodendrocyte progenitor (OP) differentiation into mature oligodendrocytes. Therefore, we questioned whether FGFR1 signaling may inhibit the capacity of OP cells to generate oligodendrocytes in a demyelinating disease model and whether genetically reducing FGFR1 signaling in oligodendrocyte lineage cells could enhance the capacity for remyelination. FGFR1 was found to be upregulated in the corpus callosum during cuprizone mediated demyelination and expressed on OP cells just prior to remyelination. Plp/CreER(T):Fgfr1(fl/fl) mice were administered tamoxifen to induce conditional Fgfr1 deletion in oligodendrocyte lineage cells. Tamoxifen administration during chronic demyelination resulted in reduced FGFR1 expression in OP cells. OP proliferation and population size were not altered one week after tamoxifen treatment. Tamoxifen was then administered during chronic demyelination and mice were given a six week recovery period without cuprizone in the chow. After the recovery period, OP numbers were reduced and the number of mature oligodendrocytes was increased, indicating an effect of FGFR1 reduction on OP differentiation. Importantly, tamoxifen administration in Plp/CreER(T):Fgfr1(fl/fl) mice significantly promoted remyelination and axon integrity. These results demonstrate a direct effect of FGFR1 signaling in oligodendrocyte lineage cells as inhibiting the repair capacity of OP cells following chronic demyelination in the adult CNS.
成年哺乳动物大脑中存在多种内源性祖细胞类型。然而，在中枢神经系统损伤或疾病后，祖细胞群体的再生能力通常不足，并且实际上可能受到损伤实质中不允许或抑制信号的限制。在成年中枢神经系统中，髓鞘再生是最有效和最简单的再生过程，但在反复或慢性脱髓鞘后仍然不足。我们之前的体外研究表明，成纤维细胞生长因子受体 1（FGFR1）信号抑制少突胶质前体细胞（OP）分化为成熟的少突胶质细胞。因此，我们质疑 FGFR1 信号是否会抑制 OP 细胞在脱髓鞘疾病模型中产生少突胶质细胞的能力，以及在少突胶质细胞谱系细胞中遗传降低 FGFR1 信号是否可以增强髓鞘再生的能力。在 cuprizone 介导的脱髓鞘过程中，FGFR1 在胼胝体中上调，并在少突胶质前体细胞开始髓鞘再生之前表达。Plp/CreER(T):Fgfr1(fl/fl) 小鼠给予他莫昔芬以诱导少突胶质细胞谱系细胞中条件性 Fgfr1 缺失。在慢性脱髓鞘期间给予他莫昔芬导致 OP 细胞中 FGFR1 表达减少。他莫昔芬处理后一周，OP 增殖和细胞数量没有改变。然后在慢性脱髓鞘期间给予他莫昔芬，并在饲料中不含 cuprizone 的情况下给予小鼠六周恢复期。恢复期后，OP 数量减少，成熟少突胶质细胞数量增加，表明 FGFR1 减少对 OP 分化有影响。重要的是，Plp/CreER(T):Fgfr1(fl/fl) 小鼠中的他莫昔芬给药显著促进了髓鞘再生和轴突完整性。这些结果表明，FGFR1 信号在少突胶质细胞谱系细胞中具有直接作用，可抑制成年中枢神经系统慢性脱髓鞘后 OP 细胞的修复能力。
