Autophagy promotes apoptosis of mesenchymal stem cells under inflammatory microenvironment.
Autophagy promotes apoptosis of mesenchymal stem cells under inflammatory microenvironment.
复制标题
自噬促进炎症微环境下间充质干细胞凋亡。
DOI：
10.1186/s13287-015-0245-4
复制
发表时间：
2015-12-15
影响因子：
7.5
通讯作者：
Wang RX
中科院分区：
文献类型：
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作者：
Dang S;Yu ZM;Zhang CY;Zheng J;Li KL;Wu Y;Qian LL;Yang ZY;Li XR;Zhang Y;Wang RX
间充质干细胞（mesenchymal stem cells, MSCs）已广泛应用于多种炎症性疾病的治疗。炎症因子可诱导间充质干细胞凋亡和自噬。然而，在炎症微环境中，自噬是否对MSCs起促或反凋亡作用尚不清楚。方法利用含有小发夹RNA的慢病毒构建MSCs，敲低beclin -1，抑制自噬，并将MSCs应用于脓毒症模型，评价MSCs的治疗效果。结果抑制MSCs自噬比对照MSCs更能提高脓毒症小鼠的存活率，并且自噬促进了MSCs在脓毒症小鼠中的凋亡。进一步研究表明，自噬可加重肿瘤坏死因子α +干扰素γ诱导的间充质干细胞凋亡。机械上，自噬通过抑制活性氧/丝裂原活化蛋白激酶1/3通路抑制促生存基因bcl -2的表达。结论炎症微环境诱导的自噬促进了间充质干细胞的凋亡。因此，调节骨髓间充质干细胞的自噬将为提高骨髓间充质干细胞在免疫治疗期间的存活率提供一种新的途径。
BackgroundMesenchymal stem cells (MSCs) have been widely applied to treat various inflammatory diseases. Inflammatory cytokines can induce both apoptosis and autophagy in MSCs. However, whether autophagy plays a pro- or con-apoptosis effect on MSCs in an inflammatory microenvironment has not been clarified.MethodsWe inhibited autophagy by constructing MSCs with lentivirus containing small hairpin RNA to knockdownBeclin-1and applied these MSCs to a model of sepsis to evaluate therapeutic effect of MSCs.ResultsHere we show that inhibition of autophagy in MSCs increases the survival rate of septic mice more than control MSCs, and autophagy promotes apoptosis of MSCs during application to septic mice. Further study demonstrated that autophagy aggravated tumor necrosis factor alpha plus interferon gamma-induced apoptosis of MSCs. Mechanically, autophagy inhibits the expression of the pro-survival geneBcl-2via suppressing reactive oxygen species/mitogen-activated protein kinase 1/3 pathway.ConclusionsOur findings indicate that an inflammatory microenvironment-induced autophagy promotes apoptosis of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel approach to improve MSC survival during immunotherapy.