Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis.
Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis.
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来自人诱导多能干细胞来源的间充质基质细胞 (hiPSC-MSC) 的细胞外囊泡通过传递特异性蛋白 (SP1) 和鞘氨醇激酶的转录激活来防止肾缺血/再灌注损伤
DOI：
10.1038/s41419-017-0041-4
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发表时间：
2017-12-11
影响因子：
9
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Yuan X;Li D;Chen X;Han C;Xu L;Huang T;Dong Z;Zhang M
肾缺血再灌注是急性肾损伤(AKI)的主要原因之一，与高死亡率相关。在此，我们证明了hPSC-MSCs分泌的细胞外小泡(EVS)在肾脏I/R损伤保护中起着关键作用。HiPSC-MSCs-Evs可以与肾细胞融合，将SP1送入靶细胞，进而激活SK1的表达，增加S1P的形成。染色质免疫沉淀(ChIP)分析和荧光素酶分析证实SP1直接与SK1启动子区域结合并促进启动子活性。此外，SP1抑制(MIT)或SK1抑制(SKI-II)可完全阻断HiPSC-MSCs-EVS对大鼠I/R损伤模型的肾脏保护作用。然而，NEC-1治疗前与单独使用HiPSC-MSCs-EVS相比无明显差异。然后，我们通过CRISPR/Cas9系统建立了SP1基因敲除的HiPSC-MSC细胞系，发现SP1基因敲除后不能显示出HiPSC-MSCs-EVS的保护作用，除非在体内外通过Ad-SP1恢复SP1的水平。综上所述，本研究揭示了hPSC-MSCs-EV通过将SP1导入靶肾细胞，并在细胞内激活SK1的表达和S1P的产生，从而发挥抗肾I/R损伤的作用。这些发现提示了一种防止I/R损伤的新的肾脏保护机制，并为各种肾脏疾病和肾移植提供了潜在的治疗方法。
Renal ischemia-reperfusion is a main cause of acute kidney injury (AKI), which is associated with high mortality. Here we show that extracellular vesicles (EVs) secreted from hiPSC-MSCs play a critical role in protection against renal I/R injury. hiPSC-MSCs-EVs can fuse with renal cells and deliver SP1 into target cells, subsequently active SK1 expression and increase S1P formation. Chromatin immunoprecipitation (ChIP) analyses and luciferase assay were used to confirm SP1 binds directly to the SK1 promoter region and promote promoter activity. Moreover, SP1 inhibition (MIT) or SK1 inhibition (SKI-II) completely abolished the renal protective effect of hiPSC-MSCs-EVs in rat I/R injury mode. However, pre-treatment of necroptosis inhibitor Nec-1 showed no difference with the administration of hiPSC-MSCs-EVs only. We then generated an SP1 knockout hiPSC-MSC cell line by CRISPR/Cas9 system and found that SP1 knockout failed to show the protective effect of hiPSC-MSCs-EVs unless restoring the level of SP1 by Ad-SP1 in vitro and in vivo. In conclusion, this study describes an anti-necroptosis effect of hiPSC-MSCs-EVs against renal I/R injury via delivering SP1 into target renal cells and intracellular activating the expression of SK1 and the generation of S1P. These findings suggest a novel mechanism for renal protection against I/R injury, and indicate a potential therapeutic approach for a variety of renal diseases and renal transplantation.
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