Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity
Gaining a better understanding of autoprotection against drug-induced liver injury (DILI) may provide new strategies for its prevention and therapy. However, little is known about the underlying mechanisms of this phenomenon. We used single-cell RNA sequencing to characterize the dynamics and functi...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Journal of Pharmaceutical Analysis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2095177923000928 |
| _version_ | 1797733066826842112 |
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| author | Lingqi Yu Jun Yan Yingqi Zhan Anyao Li Lidan Zhu Jingyang Qian Fanfan Zhou Xiaoyan Lu Xiaohui Fan |
| author_facet | Lingqi Yu Jun Yan Yingqi Zhan Anyao Li Lidan Zhu Jingyang Qian Fanfan Zhou Xiaoyan Lu Xiaohui Fan |
| author_sort | Lingqi Yu |
| collection | DOAJ |
| description | Gaining a better understanding of autoprotection against drug-induced liver injury (DILI) may provide new strategies for its prevention and therapy. However, little is known about the underlying mechanisms of this phenomenon. We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells (NPCs) in autoprotection against DILI, using acetaminophen (APAP) as a model drug. Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice, followed by a higher dose in a secondary challenge. NPC subsets and dynamic changes were identified in the APAP (hepatotoxicity-sensitive) and APAP-resistant (hepatotoxicity-resistant) groups. A chemokine (C-C motif) ligand 2+ endothelial cell subset almost disappeared in the APAP-resistant group, and an R-spondin 3+ endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection. Moreover, the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation. DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group. In addition, the natural killer cell subsets NK-3 and NK-4 and the Sca-1–CD62L+ natural killer T cell subset may promote autoprotection through interferon-γ-dependent pathways. Furthermore, macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity. Overall, this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution. |
| first_indexed | 2024-03-12T12:23:41Z |
| format | Article |
| id | doaj.art-663cbbe0f7a04ce4b53931a556223875 |
| institution | Directory Open Access Journal |
| issn | 2095-1779 |
| language | English |
| last_indexed | 2024-03-12T12:23:41Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmaceutical Analysis |
| spelling | doaj.art-663cbbe0f7a04ce4b53931a5562238752023-08-30T05:50:23ZengElsevierJournal of Pharmaceutical Analysis2095-17792023-08-01138926941Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicityLingqi Yu0Jun Yan1Yingqi Zhan2Anyao Li3Lidan Zhu4Jingyang Qian5Fanfan Zhou6Xiaoyan Lu7Xiaohui Fan8Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, Zhejiang, 314100, ChinaPharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, ChinaPharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, ChinaPharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, Zhejiang, 314100, ChinaPharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, ChinaPharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, Zhejiang, 314100, ChinaSchool of Pharmacy, The University of Sydney, Sydney, 2006, AustraliaPharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, Zhejiang, 314100, China; Innovation Center in Zhejiang University, State Key Laboratory of Component-Based Chinese Medicine, Hangzhou 310058, China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang, 321016, China; Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou, 310058, China; Corresponding author. Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, Zhejiang, 314100, China; Innovation Center in Zhejiang University, State Key Laboratory of Component-Based Chinese Medicine, Hangzhou 310058, China; Jinhua Institute of Zhejiang University, Jinhua, Zhejiang, 321016, China; Corresponding author. Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.Gaining a better understanding of autoprotection against drug-induced liver injury (DILI) may provide new strategies for its prevention and therapy. However, little is known about the underlying mechanisms of this phenomenon. We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells (NPCs) in autoprotection against DILI, using acetaminophen (APAP) as a model drug. Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice, followed by a higher dose in a secondary challenge. NPC subsets and dynamic changes were identified in the APAP (hepatotoxicity-sensitive) and APAP-resistant (hepatotoxicity-resistant) groups. A chemokine (C-C motif) ligand 2+ endothelial cell subset almost disappeared in the APAP-resistant group, and an R-spondin 3+ endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection. Moreover, the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation. DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group. In addition, the natural killer cell subsets NK-3 and NK-4 and the Sca-1–CD62L+ natural killer T cell subset may promote autoprotection through interferon-γ-dependent pathways. Furthermore, macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity. Overall, this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.http://www.sciencedirect.com/science/article/pii/S2095177923000928Single-cell RNA sequencingDrug-induced liver injuryAutoprotection against APAP hepatotoxicityEndothelial cellsDendritic cells |
| spellingShingle | Lingqi Yu Jun Yan Yingqi Zhan Anyao Li Lidan Zhu Jingyang Qian Fanfan Zhou Xiaoyan Lu Xiaohui Fan Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity Journal of Pharmaceutical Analysis Single-cell RNA sequencing Drug-induced liver injury Autoprotection against APAP hepatotoxicity Endothelial cells Dendritic cells |
| title | Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity |
| title_full | Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity |
| title_fullStr | Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity |
| title_full_unstemmed | Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity |
| title_short | Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity |
| title_sort | single cell rna sequencing reveals the dynamics of hepatic non parenchymal cells in autoprotection against acetaminophen induced hepatotoxicity |
| topic | Single-cell RNA sequencing Drug-induced liver injury Autoprotection against APAP hepatotoxicity Endothelial cells Dendritic cells |
| url | http://www.sciencedirect.com/science/article/pii/S2095177923000928 |
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