Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury

间充质干细胞 外体 细胞生物学 肝损伤 化学 癌症研究 微泡 生物 药理学 生物化学 小RNA 基因
作者
Feiyan Lin,Wenyi Chen,Jiahang Zhou,Jiaqi Zhu,Qigu Yao,Bing Feng,Xudong Feng,Xiaowei Shi,Qiaoling Pan,Jiong Yu,Lanjuan Li,Hongcui Cao
出处
期刊:Cell Death and Disease [Springer Nature]
卷期号:13 (3) 被引量:110
标识
DOI:10.1038/s41419-022-04708-w
摘要

Abstract Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate liver injury. Here, the protective effect of MSCs on carbon tetrachloride (CCl 4 )-induced acute liver injury (ALI) was investigated. In this study, we illustrated a novel mechanism that ferroptosis, a newly recognized form of regulated cell death, contributed to CCl 4 -induced ALI. Subsequently, based on the in vitro and in vivo evidence that MSCs and MSC-derived exosomes (MSC-Exo) treatment achieved pathological remission and inhibited the production of lipid peroxidation, we proposed an MSC-based therapy for CCl 4 -induced ALI. More intriguingly, treatment with MSCs and MSC-Exo downregulated the mRNA level of prostaglandin-endoperoxide synthase 2 ( Ptgs2 ) and lipoxygenases ( LOXs ) while it restored the protein level of SLC7A11 in primary hepatocytes and mouse liver, indicating that the inhibition of ferroptosis partly accounted for the protective effect of MSCs and MSC-Exo on ALI. We further revealed that MSC-Exo-induced expression of SLC7A11 protein was accompanied by increasing of CD44 and OTUB1. The aberrant expression of ubiquitinated SLC7A11 triggered by CCl 4 could be rescued with OTUB1-mediated deubiquitination, thus strengthening SLC7A11 stability and thereby leading to the activation of system X C − to prevent CCl 4 -induced hepatocyte ferroptosis. In conclusion, we showed that MSC-Exo had a protective role against ferroptosis by maintaining SLC7A11 function, thus proposing a novel therapeutic strategy for ferroptosis-induced ALI.
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