Abstract
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.
Highlights
Medicine, Shanghai Jiao Tong University, Shanghai, China 2Department of Hepatic Surgery, Ren Ji Hospital, School of Medicine, ShanghaiRenal ischemia followed by reperfusion (I/R), caused by circulatory shock of different etiologies, or by anesthesia, surgery, or transplantation, is a major cause ofJiao Tong University, Shanghai, China Full list of author information is available at the end of the article acute renal failure (ARF)[1,2]
The hiPSCMSCs-extracellular vesicles (EVs) can directly delivery specificity protein 1 (SP1) into renal cells and inhibit necroptosis via transcriptional activation of SK1 expression and generation of S1P. These findings largely extend our current understanding of human-induced pluripotent stem cells (hiPSCs)-mesenchymal stem cells (MSCs)-derived EVs, and suggest that they may function to restore renal function after injury, dysfunction, or disease
Because this positive functional effect was accompanied by rapid disappearance of administered MSCs from the kidney, it is supposed that these cells act principally through paracrine mechanisms, especially MSCs-derived EVs51–55
Summary
Shanghai Jiao Tong University, Shanghai, China 2Department of Hepatic Surgery, Ren Ji Hospital, School of Medicine, ShanghaiRenal ischemia followed by reperfusion (I/R), caused by circulatory shock of different etiologies, or by anesthesia, surgery, or transplantation, is a major cause ofJiao Tong University, Shanghai, China Full list of author information is available at the end of the article acute renal failure (ARF)[1,2]. Yuan et al Cell Death and Disease (2017)8:3200 therapies, the mortality associated with AKI remains high[3,4]. Our limited understanding of the complex cell death mechanism in the process of AKI impedes the development of desirable therapeutics[5]. Apoptosis was recognized as the main form of cell death that is responsible for renal dysfunction in AKI6. Despite the substantial therapeutic effect in animal models, the efficient anti-apoptosis intervention strategies are still absented in clinic. This could be partly ascribed to our limited understanding of the complex cell death mechanism in the process of AKI. The signaling pathways and main regulators of necroptosis in the process of AKI remain unclear
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