University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, USA.
J Neuroinflammation. 2012 Aug 11;9:195. doi: 10.1186/1742-2094-9-195.
Reactive astrogliosis is a ubiquitous but poorly understood hallmark of central nervous system pathologies such as trauma and neurodegenerative diseases. In vitro and in vivo studies have identified proinflammatory cytokines and chemokines as mediators of astrogliosis during injury and disease; however, the molecular mechanism remains unclear. In this study, we identify astrocyte elevated gene-1 (AEG-1), a human immunodeficiency virus 1 or tumor necrosis factor α-inducible oncogene, as a novel modulator of reactive astrogliosis. AEG-1 has engendered tremendous interest in the field of cancer research as a therapeutic target for aggressive tumors. However, little is known of its role in astrocytes and astrocyte-mediated diseases. Based on its oncogenic role in several cancers, here we investigate the AEG-1-mediated regulation of astrocyte migration and proliferation during reactive astrogliosis.
An in vivo brain injury mouse model was utilized to show AEG-1 induction following reactive astrogliosis. In vitro wound healing and cell migration assays following AEG-1 knockdown were performed to analyze the role of AEG-1 in astrocyte migration. AEG-1-mediated regulation of astrocyte proliferation was assayed by quantifying the levels of cell proliferation markers, Ki67 and proliferation cell nuclear antigen, using immunocytochemistry. Confocal microscopy was used to evaluate nucleolar localization of AEG-1 in cultured astrocytes following injury.
The in vivo mouse model for brain injury showed reactive astrocytes with increased glial fibrillary acidic protein and AEG-1 colocalization at the wound site. AEG-1 knockdown in cultured human astrocytes significantly reduced astrocyte migration into the wound site and cell proliferation. Confocal analysis showed colocalization of AEG-1 to the nucleolus of injured cultured human astrocytes.
The present findings report for the first time the novel role of AEG-1 in mediating reactive astrogliosis and in regulating astrocyte responses to injury. We also report the nucleolar localization of AEG-1 in human astrocytes in response to injury. Future studies may be directed towards elucidating the molecular mechanism of AEG-1 action in astrocytes during reactive astrogliosis.
反应性星形胶质细胞增生是中枢神经系统病变（如创伤和神经退行性疾病）的普遍但了解甚少的标志。体外和体内研究已经确定促炎细胞因子和趋化因子是损伤和疾病期间星形胶质细胞增生的介质；然而，分子机制尚不清楚。在这项研究中，我们确定了星形细胞上调基因-1（AEG-1），一种人类免疫缺陷病毒 1 或肿瘤坏死因子 α 诱导的癌基因，作为反应性星形胶质细胞增生的新型调节剂。AEG-1 作为侵袭性肿瘤的治疗靶点，在癌症研究领域引起了极大的兴趣。然而，人们对其在星形胶质细胞和星形胶质细胞介导的疾病中的作用知之甚少。基于其在几种癌症中的致癌作用，我们在这里研究了 AEG-1 在反应性星形胶质细胞增生过程中对星形胶质细胞迁移和增殖的调节作用。
利用体内脑损伤小鼠模型显示反应性星形胶质细胞增生后 AEG-1 的诱导。进行 AEG-1 敲低后的体外伤口愈合和细胞迁移实验，以分析 AEG-1 在星形胶质细胞迁移中的作用。通过免疫细胞化学定量测定细胞增殖标志物 Ki67 和增殖细胞核抗原的水平，检测 AEG-1 对星形胶质细胞增殖的调节作用。利用共聚焦显微镜评估损伤后培养的星形胶质细胞中 AEG-1 的核仁定位。
体内脑损伤小鼠模型显示，伤灶处反应性星形胶质细胞中 GFAP 和 AEG-1 共定位增加。培养的人星形胶质细胞中 AEG-1 的敲低显著减少了星形胶质细胞向伤口部位的迁移和细胞增殖。共聚焦分析显示，AEG-1 与损伤培养的人星形胶质细胞的核仁共定位。
本研究首次报道了 AEG-1 在介导反应性星形胶质细胞增生和调节星形胶质细胞对损伤的反应中的新作用。我们还报告了人类星形胶质细胞在受到损伤时 AEG-1 向核仁的定位。未来的研究可能旨在阐明 AEG-1 在反应性星形胶质细胞增生过程中在星形胶质细胞中的作用的分子机制。
