Nitric Oxide Stimulates the Proliferation of Neural Stem Cells Bypassing the Epidermal Growth Factor Receptor
Nitric Oxide Stimulates the Proliferation of Neural Stem Cells Bypassing the Epidermal Growth Factor Receptor
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DOI：
10.1002/stem.444
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发表时间：
2010-07-01
期刊：
影响因子：
5.2
通讯作者：
Araujo, Ines Maria
中科院分区：
文献类型：
--
作者：
Carreira, Bruno Pereira;Morte, Maria Ines;Araujo, Ines Maria
一氧化氮(NO)可抑制神经干细胞的增殖。一些证据表明，在某些条件下，NO也可以促进细胞增殖，尽管NO在神经干细胞中潜在的增殖效应的机制尚未阐明。在这项工作中，我们研究和表征了NO在小鼠脑室下区细胞培养中的增殖作用。我们发现，NO供体NOC-18(10 MU M)促进细胞增殖，而高浓度(100 MU M)则抑制细胞增殖。在暴露于NO后，细胞增殖迅速增加，并通过阻断丝裂原激活的激酶(MAPK)途径而被阻止，而不依赖于表皮生长因子(EGF)受体。在EGF受体下游，NO激活了p21Ras和MAPK通路，导致细胞周期蛋白依赖性激酶抑制因子I，p27(KIP1)的核存在减少，从而允许细胞周期的进展。此外，在显示癫痫损伤后海马区神经干细胞增殖增加的小鼠模型中，我们观察到诱导型一氧化氮合酶(iNOS(-/-)小鼠)的缺失阻止了野生型小鼠癫痫发作后观察到的细胞增殖的增加，表明iNOS来源的NO对于脑损伤后细胞增殖的增加是重要的。总体而言，我们发现NO能够通过绕过EGF受体刺激神经干细胞的增殖，并促进细胞分裂。此外，在体内的病理生理条件下，iNOS来源的NO也促进了海马区的增殖。干细胞2010：28：1219-1230
Nitric oxide (NO) was described to inhibit the proliferation of neural stem cells. Some evidence suggests that NO, under certain conditions, can also promote cell proliferation, although the mechanisms responsible for a potential proliferative effect of NO in neural stem cells have remained unaddressed. In this work, we investigated and characterized the proliferative effect of NO in cell cultures obtained from the mouse subventricular zone. We found that the NO donor NOC-18 (10 mu M) increased cell proliferation, whereas higher concentrations (100 mu M) inhibited cell proliferation. Increased cell proliferation was detected rapidly following exposure to NO and was prevented by blocking the mitogen-activated kinase (MAPK) pathway, independently of the epidermal growth factor (EGF) receptor. Downstream of the EGF receptor, NO activated p21Ras and the MAPK pathway, resulting in a decrease in the nuclear presence of the cyclin-dependent kinase inhibitor I, p27(KIP1), allowing for cell cycle progression. Furthermore, in a mouse model that shows increased proliferation of neural stem cells in the hippocampus following seizure injury, we observed that the absence of inducible nitric oxide synthase (iNOS(-/-) mice) prevented the increase in cell proliferation observed following seizures in wild-type mice, showing that NO from iNOS origin is important for increased cell proliferation following a brain insult. Overall, we show that NO is able to stimulate the proliferation of neural stem cells bypassing the EGF receptor and promoting cell division. Moreover, under pathophysiological conditions in vivo, NO from iNOS origin also promotes proliferation in the hippocampus. STEM CELLS 2010:28:1219-1230