Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 lida-nishi, Yamagata 990-9585, Japan; Department of Neurosurgery, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
Neurosci Lett. 2010 Feb 12;470(2):115-20. doi: 10.1016/j.neulet.2009.12.067. Epub 2010 Jan 1.
Control of stem cell state and differentiation of neural stem/progenitor cells is essential for proper development of the nervous system. EGF and FGF2 play important roles in the control of neural stem/progenitor cells, but the underlying mechanism still remains unclear. Here we show, using in vitro primary cultures of mouse neural stem/progenitor cells, that both PI3K and mTOR are activated by EGF/FGF2 but that inhibiting the activation of either PI3K or mTOR alone results in only reduced proliferation of neural stem/progenitor cells without affecting their stem cell state, namely, the capacity to self-renew. However, significantly, concurrent inhibition of PI3K and mTOR promoted exit from the stem cell state together with astrocytic differentiation of neural stem/progenitor cells. These findings suggest that PI3K and mTOR are involved in the EGF/FGF2-mediated maintenance of neural stem/progenitor cells and that they may act in parallel and independent pathways, complementing and backing up each other to maintain the stem cell state.
控制干细胞状态和神经干细胞/祖细胞的分化对于神经系统的正常发育至关重要。EGF 和 FGF2 在神经干细胞/祖细胞的控制中发挥重要作用，但潜在的机制仍不清楚。在这里，我们使用体外培养的小鼠神经干细胞/祖细胞表明，EGF/FGF2 可激活 PI3K 和 mTOR，但单独抑制 PI3K 或 mTOR 的激活只会导致神经干细胞/祖细胞增殖减少，而不会影响其干细胞状态，即自我更新的能力。然而，值得注意的是，PI3K 和 mTOR 的同时抑制促进了神经干细胞/祖细胞从干细胞状态退出，并伴有星形胶质细胞分化。这些发现表明，PI3K 和 mTOR 参与了 EGF/FGF2 介导的神经干细胞/祖细胞的维持，并且它们可能在平行且独立的途径中发挥作用，相互补充和支持以维持干细胞状态。
