SRT1720 promotes survival of aged human mesenchymal stem cells via FAIM: a pharmacological strategy to improve stem cell-based therapy for rat myocardial infarction.
SRT1720 promotes survival of aged human mesenchymal stem cells via FAIM: a pharmacological strategy to improve stem cell-based therapy for rat myocardial infarction.
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SRT1720 通过 FAIM 促进衰老人间充质干细胞的存活：改善基于干细胞的大鼠心肌梗死治疗的药理学策略
DOI：
10.1038/cddis.2017.107
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发表时间：
2017-04-06
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Liu X;Hu D;Zeng Z;Zhu W;Zhang N;Yu H;Chen H;Wang K;Wang Y;Wang L;Zhao J;Zhang L;Wu R;Hu X;Wang J
SIRT1已被证明可以使老年大鼠间充质干细胞（MSCs）复壮并提高其治疗效果。在此，我们研究了SIRT1激活剂SRT 1720预处理对老年人MSC（hMSC）的保护作用。通过检测血清剥夺+缺氧+ ±500 μM过氧化氢（H2O2）对老化hMSCs存活的影响，确定老化hMSCs的最佳预处理条件为0.5 μM SRT 1720处理24h。这些条件下的预处理增加了老年hMSCs的存活1天（2.7倍）和3天（1.9倍）后，被移植到大鼠心肌梗死（MI）模型结扎左前降支（LAD）冠状动脉。与DMSO预处理组相比，MI后28天，用SRT 1720预处理的老龄hMSC移植实现了大鼠心脏左心室射血分数（58.9±3.6 vs 52.8±5%）和血管生成的增加，以及纤维化的减少。在氧化应激下对老化的hMSC进行的无偏转录组分析表明，Fas凋亡抑制分子（FAIM）在SRT 1720预处理后显著上调（14.9±0.2倍）。此外，SRT 1720的抗凋亡作用通过用小干扰RNA靶向的FAIM敲低FAIM而减轻。这些结果表明，SRT 1720预处理改善了老化hMSCs的存活，并增强了其对大鼠心肌梗死（MI）的治疗效果。FAIM的上调可能参与了其保护作用的机制。
SIRT1 has been proved to rejuvenate and improve the therapeutic efficacy of aged rat mesenchymal stem cells (MSCs). Herein, we investigate the protective effect of pretreatment with SIRT1 activator SRT1720 on aged human MSCs (hMSCs). The optimized pretreatment condition for aged hMSCs was determined to be 0.5 μM SRT1720 for 24 h by monitoring the survival of aged hMSCs subjected to serum deprivation±hypoxia and±500 μM hydrogen peroxide (H 2 O 2). Pretreatment with these conditions increased the survival of aged hMSCs 1 day (2.7-fold) and 3 days (1.9-fold) after being transplanted into a rat myocardial infarction (MI) model created by ligation of the left anterior descending (LAD) coronary artery. Transplantation with SRT1720 pretreated aged hMSCs achieved increased left ventricular ejection fraction (58.9±3.6 versus 52.8±5%) and angiogenesis with reduced fibrosis of rat hearts as compared to DMSO pretreated group 28 days following MI. Unbiased transcriptome analysis conducted on aged hMSCs under oxidative stress indicated the Fas apoptosis inhibitory molecule (FAIM) was significantly upregulated following SRT1720 pretreatment (14.9±0.2-folds). Moreover, the anti-apoptotic effect of SRT1720 was mitigated by FAIM knockdown with a small interfering RNA-targeted FAIM. These results indicated that pretreatment with SRT1720 improves survival of aged hMSCs, and enhances their therapeutic efficacy for rat myocardial infarction (MI). Upregulation of FAIM possibly involves in the mechanisms of the protective effects.