Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury
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 promi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/1/158 |
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| author | Yelei Cen Guohua Lou Jinjin Qi Minwei Li Min Zheng Yanning Liu |
| author_facet | Yelei Cen Guohua Lou Jinjin Qi Minwei Li Min Zheng Yanning Liu |
| author_sort | Yelei Cen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T13:46:36Z |
| format | Article |
| id | doaj.art-d2322450c68a4fb1940a8fc9b64f0f23 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T13:46:36Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-d2322450c68a4fb1940a8fc9b64f0f232023-11-30T20:59:08ZengMDPI AGAntioxidants2076-39212023-01-0112115810.3390/antiox12010158Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver InjuryYelei Cen0Guohua Lou1Jinjin Qi2Minwei Li3Min Zheng4Yanning Liu5The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, ChinaThe State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, ChinaThe State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, ChinaThe State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, ChinaThe State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, ChinaThe State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, ChinaAcetaminophen (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.https://www.mdpi.com/2076-3921/12/1/158mesenchymal stem cellAPAP-induced liver injurymitochondria retrogradeROSDNA damage |
| spellingShingle | Yelei Cen Guohua Lou Jinjin Qi Minwei Li Min Zheng Yanning Liu Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury Antioxidants mesenchymal stem cell APAP-induced liver injury mitochondria retrograde ROS DNA damage |
| title | Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury |
| title_full | Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury |
| title_fullStr | Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury |
| title_full_unstemmed | Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury |
| title_short | Adipose-Derived Mesenchymal Stem Cells Inhibit JNK-Mediated Mitochondrial Retrograde Pathway to Alleviate Acetaminophen-Induced Liver Injury |
| title_sort | adipose derived mesenchymal stem cells inhibit jnk mediated mitochondrial retrograde pathway to alleviate acetaminophen induced liver injury |
| topic | mesenchymal stem cell APAP-induced liver injury mitochondria retrograde ROS DNA damage |
| url | https://www.mdpi.com/2076-3921/12/1/158 |
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