Adipose-derived mesenchymal stem cells protect PC12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of XIAP through P13-K/Akt activation
Adipose-derived mesenchymal stem cells protect PC12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of XIAP through P13-K/Akt activation
复制标题
脂肪来源的间充质干细胞通过 PI3-K/Akt 激活上调 XIAP，保护 PC12 细胞免受谷氨酸兴奋性毒性诱导的细胞凋亡。
DOI：
10.1016/j.tox.2010.10.011
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发表时间：
2011-01-11
期刊：
影响因子：
4.5
通讯作者：
Zhao, Robert Chunhua
中科院分区：
文献类型：
--
作者：
Lu, Shan;Lu, Chunhua;Zhao, Robert Chunhua
谷氨酸兴奋性毒性是神经元凋亡的重要因素之一，与许多神经退行性疾病有关。以往的研究表明，间充质干细胞有能力保护培养的神经元免受兴奋性毒性诱导的凋亡，但其机制尚不清楚。在这项研究中，我们评估了脂肪间充质干细胞（AMSCs）是否可以通过分泌神经营养因子来保护PC 12细胞免受谷氨酸诱导的损伤。我们发现AMSC在常氧和缺氧条件下均分泌神经营养因子，包括血管内皮生长因子（VEGF）、肝细胞生长因子（HGF）、脑源性神经营养因子（BDNF）和神经生长因子（NGF）。AMSC条件培养基（AMSC-CM）对兴奋性毒性损伤的PC 12细胞具有保护作用，表现为细胞活力增加、TUNEL染色阳性核数目减少和caspase-3活性降低。通过中和性单克隆抗体和特异性抑制剂的筛选，证实VEGF、HGF和BDNF是AMSC作用的介质，并参与了PI 3-K/Akt和MAPK通路。Western blot分析显示AMSC-CM可上调PC 12细胞p-Akt表达，上调XIAP表达，降低c-caspase-3表达。这些结果表明，AMSC可以有效地保护PC 12细胞免受谷氨酸兴奋性毒性诱导的凋亡，并支持AMSC可能是一种有用的治疗中风或神经退行性疾病，往往涉及兴奋性毒性的假设。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Glutamate excitotoxicity has been implicated as one of the factors contributing to neuronal apoptosis and is involved in many neurodegenerative diseases. Previous studies suggest that mesenchymal stem cells have the ability to protect cultured neurons from excitotoxicity-induced apoptosis, although the underlying mechanisms are not clear. In this study, we evaluated whether adipose mesenchymal stem cells (AMSCs) could protect against glutamate-induced injury in PC12 cells by secreting neurotrophic factors. We found that AMSCs secreted neurotrophic factors including vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) under both normoxic and hypoxic conditions. AMSC - conditioned medium (AMSC-CM) had a protective effect on excitotoxicity-injured PC12 cells, as indicated by increased cell viability, decreased number of TUNEL-staining positive nuclei and lowered caspase-3 activity. By using neutralizing monoclonal antibodies and specific inhibitors, VEGF, HGF and BDNF were identified as the mediators of AMSC effects and PI3-K/Akt and MAPK pathways were involved. Western blot analysis showed that AMSC-CM can increase the level of p-Akt, up-regulate XIAP and reduce the level of cleaved-caspase-3 in PC12 cells. These results suggest that AMSCs can effectively protect PC12 cells from glutamate excitotoxicity-induced apoptosis and support the hypothesis that AMSCs may be a useful treatment for stroke or neurodegenerative diseases which often involve excitotoxicity. (C) 2010 Elsevier Ireland Ltd. All rights reserved.