Ischemic Preconditioning Augments Survival of Stem Cells via miR-210 Expression by Targeting Caspase-8-associated Protein 2
Ischemic Preconditioning Augments Survival of Stem Cells via miR-210 Expression by Targeting Caspase-8-associated Protein 2
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DOI：
10.1074/jbc.m109.020925
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发表时间：
2009-11-27
影响因子：
4.8
通讯作者：
Ashraf, Muhammad
中科院分区：
文献类型：
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作者：
Kim, Ha Won;Haider, Husnain K.;Ashraf, Muhammad
微小RNA（miRs）通过转录后调节基因表达参与大多数细胞功能，尽管关于它们在干细胞缺血预处理（IP）中的作用的信息很少。我们报告说，IP骨髓间充质干细胞（MSC）与两个周期的30分钟缺血/复氧（I/R）支持他们的生存下随后更长时间暴露于缺氧和以下植入梗死心脏。IP通过激活Akt（Ser（473））和ERK 1/2（Thr（202）/Tyr（204））以及低氧诱导因子-1 α（HIF-1 α）的核转位显著减少MSC的凋亡。我们观察到预处理的MSC（（MSC）-M-PC）中miR-210的伴随诱导。抑制HIF-1 α或miR-210可消除预处理的细胞保护作用。将这些数据外推到急性心肌梗死大鼠模型的体内研究中，主要是通过miR-210的作用改善了移植后的干细胞存活率。值得注意的是，与相同持续时间的单周期缺氧相比，多个I/R周期更有效地调节miR-210，从而促进MSC存活。大鼠凋亡基因的真实的实时PCR阵列、计算靶基因分析和荧光素酶报告基因测定鉴定了（MSC）-M-PC中的FLICE相关巨大蛋白（FLASH）/半胱天冬酶-8相关蛋白-2（Casp 8ap 2）为miR-210的靶基因。在miR-210敲低的（MSC）-M-PC中诱导FLASH/CASP 8AP 2导致细胞凋亡增加。总之，这些数据表明IP提供的细胞保护作用通过FLASH/Casp 8ap 2抑制由miR 210诱导调节。这些结果强调了通过多次短暂I/R的IP是促进干细胞存活的新策略。
MicroRNAs (miRs) participate in most cellular functions by posttranscriptional regulation of gene expression albeit with little information regarding their role in ischemic preconditioning (IP) of stem cells. We report that IP of bone marrow-derived mesenchymal stem cells (MSCs) with two cycles of 30-min ischemia/reoxygenation (I/R) supported their survival under subsequent longer exposure to anoxia and following engraftment in the infarcted heart. IP significantly reduced apoptosis in MSCs through activation of Akt (Ser(473)) and ERK1/2 (Thr(202)/Tyr(204)) and nuclear translocation of hypoxia-inducible factor-1 alpha (HIF-1 alpha). We observed concomitant induction of miR-210 in the preconditioned MSCs ((MSCs)-M-PC). Inhibition of HIF-1 alpha or of miR-210 abrogated the cytoprotective effects of preconditioning. Extrapolation of these data to in vivo studies in a rat model of acute myocardial infarction predominantly improved stem cell survival after engraftment with a role for miR-210. Notably, multiple I/R cycles more effectively regulated the miR-210 and hence promoted MSC survival compared with single-cycle hypoxia of an equal duration. Real time PCR array for rat apoptotic genes, computational target gene analyses, and luciferase reporter assay identified FLICE-associated huge protein (FLASH)/caspase-8-associated protein-2 (Casp8ap2) in (MSCs)-M-PC as the target gene of miR-210. Induction of FLASH/CASP8AP2 in miR-210 knocked-down (MSCs)-M-PC resulted in increased cell apoptosis. Taken together, these data demonstrated that cytoprotection afforded by IP was regulated by miR210 induction via FLASH/Casp8ap2 suppression. These results highlighted that IP by multiple short episodes of I/R is a novel strategy to promote stem cell survival.