Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse Model
Activated hepatic stellate cells (HSCs) play a detrimental role in liver fibrosis progression. Natural killer (NK) cells are known to selectively recognize abnormal or transformed cells via their receptor activation and induce target cell apoptosis and, therefore, can be used as a potential therapeu...
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MDPI AG
2023-04-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/4/1090 |
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| author | Ho Rim Oh Min Kyung Ko Daehee Son Young Wook Ki Shin-Il Kim Seok-Yong Lee Keon Wook Kang Gi Jeong Cheon Do Won Hwang Hyewon Youn |
| author_facet | Ho Rim Oh Min Kyung Ko Daehee Son Young Wook Ki Shin-Il Kim Seok-Yong Lee Keon Wook Kang Gi Jeong Cheon Do Won Hwang Hyewon Youn |
| author_sort | Ho Rim Oh |
| collection | DOAJ |
| description | Activated hepatic stellate cells (HSCs) play a detrimental role in liver fibrosis progression. Natural killer (NK) cells are known to selectively recognize abnormal or transformed cells via their receptor activation and induce target cell apoptosis and, therefore, can be used as a potential therapeutic strategy for liver cirrhosis. In this study, we examined the therapeutic effects of NK cells in the carbon tetrachloride (CCl<sub>4</sub>)-induced liver cirrhosis mouse model. NK cells were isolated from the mouse spleen and expanded in the cytokine-stimulated culture medium. Natural killer group 2, member D (NKG2D)-positive NK cells were significantly increased after a week of expansion in culture. The intravenous injection of NK cells significantly alleviated liver cirrhosis by reducing collagen deposition, HSC marker activation, and macrophage infiltration. For in vivo imaging, NK cells were isolated from codon-optimized luciferase-expressing transgenic mice. Luciferase-expressing NK cells were expanded, activated and administrated to the mouse model to track them. Bioluminescence images showed increased accumulation of the intravenously inoculated NK cells in the cirrhotic liver of the recipient mouse. In addition, we conducted QuantSeq 3′ mRNA sequencing-based transcriptomic analysis. From the transcriptomic analysis, 33 downregulated genes in the extracellular matrix (ECM) and 41 downregulated genes involved in the inflammatory response were observed in the NK cell-treated cirrhotic liver tissues from the 1532 differentially expressed genes (DEGs). This result indicated that the repetitive administration of NK cells alleviated the pathology of liver fibrosis in the CCl<sub>4</sub>-induced liver cirrhosis mouse model via anti-fibrotic and anti-inflammatory mechanisms. Taken together, our research demonstrated that NK cells could have therapeutic effects in a CCl<sub>4</sub>-induced liver cirrhosis mouse model. In particular, it was elucidated that extracellular matrix genes and inflammatory response genes, which were mainly affected after NK cell treatment, could be potential targets. |
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| language | English |
| last_indexed | 2024-03-11T05:13:18Z |
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| series | Biomedicines |
| spelling | doaj.art-adfb047c9f5c4ead8cb95122f768f7042023-11-17T18:26:24ZengMDPI AGBiomedicines2227-90592023-04-01114109010.3390/biomedicines11041090Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse ModelHo Rim Oh0Min Kyung Ko1Daehee Son2Young Wook Ki3Shin-Il Kim4Seok-Yong Lee5Keon Wook Kang6Gi Jeong Cheon7Do Won Hwang8Hyewon Youn9Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of KoreaResearch & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of KoreaResearch & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of KoreaResearch & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of KoreaResearch & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of KoreaDepartment of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of KoreaDepartment of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of KoreaDepartment of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of KoreaResearch & Development Center, THERABEST, Co., Ltd., Seoul 06656, Republic of KoreaDepartment of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of KoreaActivated hepatic stellate cells (HSCs) play a detrimental role in liver fibrosis progression. Natural killer (NK) cells are known to selectively recognize abnormal or transformed cells via their receptor activation and induce target cell apoptosis and, therefore, can be used as a potential therapeutic strategy for liver cirrhosis. In this study, we examined the therapeutic effects of NK cells in the carbon tetrachloride (CCl<sub>4</sub>)-induced liver cirrhosis mouse model. NK cells were isolated from the mouse spleen and expanded in the cytokine-stimulated culture medium. Natural killer group 2, member D (NKG2D)-positive NK cells were significantly increased after a week of expansion in culture. The intravenous injection of NK cells significantly alleviated liver cirrhosis by reducing collagen deposition, HSC marker activation, and macrophage infiltration. For in vivo imaging, NK cells were isolated from codon-optimized luciferase-expressing transgenic mice. Luciferase-expressing NK cells were expanded, activated and administrated to the mouse model to track them. Bioluminescence images showed increased accumulation of the intravenously inoculated NK cells in the cirrhotic liver of the recipient mouse. In addition, we conducted QuantSeq 3′ mRNA sequencing-based transcriptomic analysis. From the transcriptomic analysis, 33 downregulated genes in the extracellular matrix (ECM) and 41 downregulated genes involved in the inflammatory response were observed in the NK cell-treated cirrhotic liver tissues from the 1532 differentially expressed genes (DEGs). This result indicated that the repetitive administration of NK cells alleviated the pathology of liver fibrosis in the CCl<sub>4</sub>-induced liver cirrhosis mouse model via anti-fibrotic and anti-inflammatory mechanisms. Taken together, our research demonstrated that NK cells could have therapeutic effects in a CCl<sub>4</sub>-induced liver cirrhosis mouse model. In particular, it was elucidated that extracellular matrix genes and inflammatory response genes, which were mainly affected after NK cell treatment, could be potential targets.https://www.mdpi.com/2227-9059/11/4/1090liver cirrhosiscarbon tetrachloride (CCl<sub>4</sub>)natural killer (NK) cellsbioluminescence imaging (BLI) |
| spellingShingle | Ho Rim Oh Min Kyung Ko Daehee Son Young Wook Ki Shin-Il Kim Seok-Yong Lee Keon Wook Kang Gi Jeong Cheon Do Won Hwang Hyewon Youn Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse Model Biomedicines liver cirrhosis carbon tetrachloride (CCl<sub>4</sub>) natural killer (NK) cells bioluminescence imaging (BLI) |
| title | Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse Model |
| title_full | Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse Model |
| title_fullStr | Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse Model |
| title_full_unstemmed | Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse Model |
| title_short | Activated Natural Killer Cell Inoculation Alleviates Fibrotic Liver Pathology in a Carbon Tetrachloride-Induced Liver Cirrhosis Mouse Model |
| title_sort | activated natural killer cell inoculation alleviates fibrotic liver pathology in a carbon tetrachloride induced liver cirrhosis mouse model |
| topic | liver cirrhosis carbon tetrachloride (CCl<sub>4</sub>) natural killer (NK) cells bioluminescence imaging (BLI) |
| url | https://www.mdpi.com/2227-9059/11/4/1090 |
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