Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells
Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells
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DOI：
10.1242/jcs.085506
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发表时间：
2011-06
影响因子：
4
通讯作者：
Yirui Sun;Jin Hu;Liangfu Zhou;S. Pollard;Austin G Smith
中科院分区：
文献类型：
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作者：
Yirui Sun;Jin Hu;Liangfu Zhou;S. Pollard;Austin G Smith
小鼠和人中枢神经系统祖细胞可以作为干细胞系离体广泛繁殖。然而，对于大鼠，由于增殖停滞和分化，体外扩增已被证明是有问题的。在这里，我们分析了建立，在贴壁培养，未分化的三能神经干细胞（NS）细胞系来自大鼠胎脑和脊髓。大鼠NS细胞总是经历生长停滞和明显的分化后，几个通道，然而，条件培养基从增殖培养可以克服这一障碍，使未分化的大鼠NS细胞的连续繁殖。我们发现休眠是由自分泌产生的骨形态发生蛋白（BMP）诱导的。因此，BMP拮抗剂noggin可以替代条件培养基以维持持续的自我更新。Noggin还可以诱导休眠细胞重新进入细胞周期，从而重新获得神经原性潜能。我们进一步表明，成纤维细胞生长因子2（FGF2）是必需的，以抑制终端星形胶质细胞分化，并保持干细胞潜能在休眠期。这些发现突出了一个外在的调节网络，包括BMP，BMP拮抗剂和FGF 2信号，支配大鼠NS细胞的增殖，休眠和分化，并可以被操纵，使长期的克隆自我更新。
Mouse and human central nervous system progenitor cells can be propagated extensively ex vivo as stem cell lines. For the rat, however, in vitro expansion has proven to be problematic owing to proliferation arrest and differentiation. Here, we analyse the establishment, in adherent culture, of undifferentiated tripotent neural stem (NS) cell lines derived from rat foetal brain and spinal cord. Rat NS cells invariably undergo growth arrest and apparent differentiation after several passages; however, conditioned medium from proliferating cultures can overcome this block, enabling continuous propagation of undifferentiated rat NS cells. We found that dormancy is induced by autocrine production of bone morphogenetic proteins (BMPs). Accordingly, the BMP antagonist noggin can replace conditioned medium to sustain continuous self-renewal. Noggin can also induce dormant cells to re-enter the cell cycle, upon which they reacquire neurogenic potential. We further show that fibroblast growth factor 2 (FGF2) is required to suppress terminal astrocytic differentiation and maintain stem cell potency during dormancy. These findings highlight an extrinsic regulatory network, comprising BMPs, BMP antagonists and FGF2 signals, that governs the proliferation, dormancy and differentiation of rat NS cells and which can be manipulated to enable long-term clonogenic self-renewal.