A stress-induced cellular aging model with postnatal neural stem cells.
A stress-induced cellular aging model with postnatal neural stem cells.
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DOI：
10.1038/cddis.2017.445
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发表时间：
2017-09-07
影响因子：
9
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Dong CM;Wang XL;Wang GM;Zhang WJ;Zhu L;Gao S;Yang DJ;Qin Y;Liang QJ;Chen YL;Deng HT;Ning K;Liang AB;Gao ZL;Xu J
衰老是指随着时间的推移，组织的物理和功能衰退，通常导致与年龄相关的退行性疾病。越来越多的证据表明，神经干细胞（NSCs）的衰老对中枢神经系统（CNS）的衰老至关重要。然而，由于缺乏适当的衰老模型，无法在合理的时间窗内进行机制研究，因此对潜在分子机制的探索受到阻碍。本研究采用羟基脲（HU）处理方法，通过增强衰老相关β-半乳糖苷酶（SA-β-gal）染色、降低细胞增殖和分化能力、增加G 0/G1期细胞阻滞、升高活性氧（ROS）水平和减少凋亡，有效诱导出生后脑室下神经干细胞经历细胞衰老。这些表型变化伴随着p16、p21和p53表达的显著增加，以及各种DNA修复途径中的关键蛋白如xrcc 2、xrcc 3和ku 70的表达降低。进一步的蛋白质组学分析表明，HU诱导的NSC衰老涉及多条途径，包括DNA损伤与修复、线粒体功能障碍和ROS水平升高等相关基因。有趣的是，补偿机制也可能已经启动，以干扰细胞凋亡信号通路，并通过下调Bcl 2相关的X蛋白（BAX）的表达，以减少细胞死亡。综上所述，我们已经成功地建立了一个细胞模型，这将是广泛的实用程序的分子探索神经干细胞衰老和老化。
Aging refers to the physical and functional decline of the tissues over time that often leads to age-related degenerative diseases. Accumulating evidence implicates that the senescence of neural stem cells (NSCs) is of paramount importance to the aging of central neural system (CNS). However, exploration of the underlying molecular mechanisms has been hindered by the lack of proper aging models to allow the mechanistic examination within a reasonable time window. In the present study, we have utilized a hydroxyurea (HU) treatment protocol and effectively induced postnatal subventricle NSCs to undergo cellular senescence as determined by augmented senescence-associated-β-galactosidase (SA-β-gal) staining, decreased proliferation and differentiation capacity, increased G0/G1 cell cycle arrest, elevated reactive oxygen species (ROS) level and diminished apoptosis. These phenotypic changes were accompanied by a significant increase in p16, p21 and p53 expression, as well as a decreased expression of key proteins in various DNA repair pathways such as xrcc2, xrcc3 and ku70. Further proteomic analysis suggests that multiple pathways are involved in the HU-induced NSC senescence, including genes related to DNA damage and repair, mitochondrial dysfunction and the increase of ROS level. Intriguingly, compensatory mechanisms may have also been initiated to interfere with apoptotic signaling pathways and to minimize the cell death by downregulating Bcl2-associated X protein (BAX) expression. Taken together, we have successfully established a cellular model that will be of broad utilities to the molecular exploration of NSC senescence and aging.
影响因子：
9
作者：
Dong CM;Wang XL;Wang GM;Zhang WJ;Zhu L;Gao S;Yang DJ;Qin Y;Liang QJ;Chen YL;Deng HT;Ning K;Liang AB;Gao ZL;Xu J
通讯作者：
Xu J