Liu Xian-Bao, Wang Jian-An, Ogle Molly E, Wei Ling
Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
J Cell Biochem. 2009 Apr 1;106(5):903-11. doi: 10.1002/jcb.22064.
Mesenchymal stem cell (MSC) transplantation is a promising approach in the therapy of ischemic heart or CNS diseases; however, the poor viability of MSCs after transplantation critically limits the efficacy of this new strategy. Prolyl hydroxylase inhibition followed by HIF-1alpha up-regulation participates in the regulation of apoptosis and cell survival, which have been shown in cancer cells and neurons. The role of prolyl hydroxylase inhibition by dimethyloxalylglycine (DMOG) in regulation of cell survival has not been investigated in MSCs. In the present investigation with MSCs, apoptosis and cell death induced by serum deprivation were assessed by caspase-3 activation and trypan blue staining, respectively. The mitochondrial apoptotic pathway and PI3K/Akt cell survival pathway were evaluated. DMOG significantly attenuated apoptosis and cell death of MSCs, stabilized HIF-1alpha and induced downstream glucose transport 1 (Glut-1) synthesis. DMOG treatment reduced mitochondrial cytochrome c release, nuclear translocation of apoptosis inducing factor (AIF), and promoted Akt phosphorylation. A specific PI3K inhibitor, wortmannin, blocked Akt phosphorylation and abrogated the beneficial effect of DMOG. These data suggest that the DMOG protection of MSCs may provide a novel approach to promote cell survival during cell stress.
间充质干细胞（MSC）移植是治疗缺血性心脏病或中枢神经系统疾病的一种有前景的方法；然而，移植后MSC的低存活率严重限制了这一新策略的疗效。脯氨酰羟化酶抑制随后HIF-1α上调参与细胞凋亡和细胞存活的调节，这在癌细胞和神经元中已得到证实。二甲基草酰甘氨酸（DMOG）抑制脯氨酰羟化酶在MSC细胞存活调节中的作用尚未得到研究。在本次对MSC的研究中，分别通过caspase-3激活和台盼蓝染色评估血清剥夺诱导的细胞凋亡和细胞死亡。评估了线粒体凋亡途径和PI3K/Akt细胞存活途径。DMOG显著减轻了MSC的细胞凋亡和细胞死亡，稳定了HIF-1α并诱导了下游葡萄糖转运蛋白1（Glut-1）的合成。DMOG处理减少了线粒体细胞色素c释放、凋亡诱导因子（AIF）的核转位，并促进了Akt磷酸化。一种特异性PI3K抑制剂渥曼青霉素阻断了Akt磷酸化并消除了DMOG的有益作用。这些数据表明，DMOG对MSC的保护作用可能为细胞应激期间促进细胞存活提供一种新方法。
