Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury

被引:7
|
作者
Cen, Yelei [1 ]
Lou, Guohua [1 ]
Qi, Jinjin [1 ]
Li, Minwei [1 ]
Zheng, Min [1 ]
Liu, Yanning [1 ]
机构
[1] Zhejiang Univ, Natl Clin Res Ctr Infect Dis,Affiliated Hosp 1, Coll Med,State Key Lab Diag & Treatment Infect Di, Collaborat Innovat Ctr Diag & Treatment Infect Di, Hangzhou 310003, Peoples R China
基金
中国国家自然科学基金;
关键词
mesenchymal stem cell; APAP-induced liver injury; mitochondria retrograde; ROS; DNA damage; STRESS; HEPATOTOXICITY; MECHANISMS; COMPLEX; CYP2E1; MOUSE; MICE;
D O I
10.3390/antiox12010158
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study was to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice were used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, Western blotting, immunofluorescence staining, and RNA sequencing assays were used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The downregulation of activated ataxia telangiectasia-mutated (ATM) and DNA damage response proteins in AMSC-treated mouse liver indicated AMSCs blocked the JNK-ATM pathway. Overall, AMSCs may be an effective treatment for AILI by inhibiting the JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.
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页数:16
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