Overexpressing cellular repressor of E1A-stimulated genes protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis by activation of PI3K/Akt
Overexpressing cellular repressor of E1A-stimulated genes protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis by activation of PI3K/Akt
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过表达 E1A 刺激基因的细胞阻遏物可通过激活 PI3K/Akt 保护间充质干细胞免受缺氧和血清剥夺诱导的细胞凋亡
DOI：
10.1007/s10495-009-0434-7
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发表时间：
2010-04-01
期刊：
影响因子：
7.2
通讯作者：
Li, Shaohua
中科院分区：
文献类型：
--
作者：
Deng, Jie;Han, Yaling;Li, Shaohua
骨髓间充质干细胞（MSCs）在心肌梗死后的修复中具有巨大的潜力。然而，移植骨髓间充质干细胞在缺血性心脏中的生存能力差，限制了其治疗潜力。e1a刺激基因的细胞抑制因子（CREG）已被确定为一种有效的细胞凋亡抑制剂。本研究旨在探讨CREG在缺氧和血清剥夺（SD）条件下对MSCs的抗凋亡作用。我们还研究了可能介导CREG作用的潜在机制。所有实验均在大鼠骨髓间充质干细胞上进行。在封闭的GENbox缺氧室中，细胞暴露于缺氧/SD诱导细胞凋亡。在缺乏或存在针对磷酸肌肽3-激酶（PI3K）的抑制剂的情况下，研究了CREG的作用。我们发现，CREG的过表达通过抑制线粒体凋亡途径，导致caspase-3的衰减，显著保护MSCs免受缺氧/ sd诱导的凋亡。此外，在缺氧/SD条件下，CREG增强了Akt磷酸化，降低了MSCs中p53的表达。PI3K/Akt抑制剂LY294002显著增加p53蛋白量，减弱CREG对MSCs的抗凋亡作用。本研究表明，CREG是一种新的有效的MSCs存活因子，因此，它可能是心肌梗死后MSCs移植到受损心脏的有用治疗辅助手段。
Bone marrow-derived mesenchymal stem cells (MSCs) have great potential for repair after myocardial infarction. However, poor viability of transplanted MSCs in the ischemic heart has limited their therapeutic potential. Cellular repressor of E1A-stimulated genes (CREG) has been identified as a potent inhibitor of apoptosis. The aim of this study was to investigate the anti-apoptotic effects of CREG on MSCs under hypoxic and serum deprivation (SD) conditions. We also investigated the potential mechanism(s) that may mediate the actions of CREG. All experiments were performed on rat bone marrow MSCs. Apoptosis was induced by exposure of cells to hypoxia/SD in a sealed GENbox hypoxic chamber. Effects of CREG were investigated in the absence or presence of inhibitors that target phosphoinositide 3-kinase (PI3K). We found that the overexpression of CREG markedly protected MSCs from hypoxia/SD-induced apoptosis through inhibition of the mitochondrial apoptotic pathway, leading to attenuation of caspase-3. Moreover, CREG enhanced Akt phosphorylation and decreased the expression of p53 in MSCs under hypoxic/SD conditions. The PI3K/Akt inhibitor LY294002 significantly increased the amount of p53 protein and attenuated the anti-apoptotic effects of CREG on MSCs. This study indicates that CREG is a novel and potent survival factor for MSCs, therefore, it may be a useful therapeutic adjunct for transplanting MSCs into damaged heart after myocardial infarction.