Generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liver
Abstract Background Mice with humanized livers are important models to study drug toxicology testing, development of hepatitis virus treatments, and hepatocyte transplantation therapy. However, the huge difference between mouse and human in size and anatomy limited the application of humanized mice...
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| Format: | Article |
| Language: | English |
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BMC
2022-03-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-022-00760-3 |
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| author | Jilong Ren Dawei Yu Jing Wang Kai Xu Yanan Xu Renren Sun Peipei An Chongyang Li Guihai Feng Ying Zhang Xiangpeng Dai Hongye Zhao Zhengzhu Wang Zhiqiang Han Haibo Zhu Yuchun Ding Xiaoyan You Xueqin Liu Meng Wu Lin Luo Ziyi Li Yong-Guang Yang Zheng Hu Hong-jiang Wei Liangpeng Ge Tang Hai Wei Li |
| author_facet | Jilong Ren Dawei Yu Jing Wang Kai Xu Yanan Xu Renren Sun Peipei An Chongyang Li Guihai Feng Ying Zhang Xiangpeng Dai Hongye Zhao Zhengzhu Wang Zhiqiang Han Haibo Zhu Yuchun Ding Xiaoyan You Xueqin Liu Meng Wu Lin Luo Ziyi Li Yong-Guang Yang Zheng Hu Hong-jiang Wei Liangpeng Ge Tang Hai Wei Li |
| author_sort | Jilong Ren |
| collection | DOAJ |
| description | Abstract Background Mice with humanized livers are important models to study drug toxicology testing, development of hepatitis virus treatments, and hepatocyte transplantation therapy. However, the huge difference between mouse and human in size and anatomy limited the application of humanized mice in investigating human diseases. Therefore, it is urgent to construct humanized livers in pigs to precisely investigate hepatocyte regeneration and human hepatocyte therapy. CRISPR/Cas9 system and somatic cell cloning technology were used to generate two pig models with FAH deficiency and exhibiting severe immunodeficiency (FAH/RAG1 and FAH/RAG1/IL2RG deficiency). Human primary hepatocytes were then successfully transplanted into the FG pig model and constructed two pigs with human liver. Results The constructed FAH/RAG1/IL2RG triple-knockout pig models were characterized by chronic liver injury and severe immunodeficiency. Importantly, the FG pigs transplanted with primary human hepatocytes produced human albumin in a time dependent manner as early as 1 week after transplantation. Furthermore, the colonization of human hepatocytes was confirmed by immunochemistry staining. Conclusions We successfully generated pig models with severe immunodeficiency that could construct human liver tissues. |
| first_indexed | 2024-12-23T13:10:58Z |
| format | Article |
| id | doaj.art-ada7db53c13c4728ab1c467af2fbfb93 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-12-23T13:10:58Z |
| publishDate | 2022-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-ada7db53c13c4728ab1c467af2fbfb932022-12-21T17:45:44ZengBMCCell & Bioscience2045-37012022-03-0112111010.1186/s13578-022-00760-3Generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liverJilong Ren0Dawei Yu1Jing Wang2Kai Xu3Yanan Xu4Renren Sun5Peipei An6Chongyang Li7Guihai Feng8Ying Zhang9Xiangpeng Dai10Hongye Zhao11Zhengzhu Wang12Zhiqiang Han13Haibo Zhu14Yuchun Ding15Xiaoyan You16Xueqin Liu17Meng Wu18Lin Luo19Ziyi Li20Yong-Guang Yang21Zheng Hu22Hong-jiang Wei23Liangpeng Ge24Tang Hai25Wei Li26State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, First Hospital, Jilin UniversityKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, First Hospital, Jilin UniversityState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, First Hospital, Jilin UniversityState Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan Agricultural UniversityKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, First Hospital, Jilin UniversityState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, First Hospital, Jilin UniversityChongqing Academy of Animal SciencesChongqing Academy of Animal SciencesChongqing Academy of Animal SciencesChongqing Academy of Animal SciencesChongqing Academy of Animal SciencesKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, First Hospital, Jilin UniversityKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, First Hospital, Jilin UniversityKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, First Hospital, Jilin UniversityState Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan Agricultural UniversityChongqing Academy of Animal SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of SciencesAbstract Background Mice with humanized livers are important models to study drug toxicology testing, development of hepatitis virus treatments, and hepatocyte transplantation therapy. However, the huge difference between mouse and human in size and anatomy limited the application of humanized mice in investigating human diseases. Therefore, it is urgent to construct humanized livers in pigs to precisely investigate hepatocyte regeneration and human hepatocyte therapy. CRISPR/Cas9 system and somatic cell cloning technology were used to generate two pig models with FAH deficiency and exhibiting severe immunodeficiency (FAH/RAG1 and FAH/RAG1/IL2RG deficiency). Human primary hepatocytes were then successfully transplanted into the FG pig model and constructed two pigs with human liver. Results The constructed FAH/RAG1/IL2RG triple-knockout pig models were characterized by chronic liver injury and severe immunodeficiency. Importantly, the FG pigs transplanted with primary human hepatocytes produced human albumin in a time dependent manner as early as 1 week after transplantation. Furthermore, the colonization of human hepatocytes was confirmed by immunochemistry staining. Conclusions We successfully generated pig models with severe immunodeficiency that could construct human liver tissues.https://doi.org/10.1186/s13578-022-00760-3Liver regenerationImmunodeficiencyGene editingDisease model |
| spellingShingle | Jilong Ren Dawei Yu Jing Wang Kai Xu Yanan Xu Renren Sun Peipei An Chongyang Li Guihai Feng Ying Zhang Xiangpeng Dai Hongye Zhao Zhengzhu Wang Zhiqiang Han Haibo Zhu Yuchun Ding Xiaoyan You Xueqin Liu Meng Wu Lin Luo Ziyi Li Yong-Guang Yang Zheng Hu Hong-jiang Wei Liangpeng Ge Tang Hai Wei Li Generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liver Cell & Bioscience Liver regeneration Immunodeficiency Gene editing Disease model |
| title | Generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liver |
| title_full | Generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liver |
| title_fullStr | Generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liver |
| title_full_unstemmed | Generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liver |
| title_short | Generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liver |
| title_sort | generation of immunodeficient pig with hereditary tyrosinemia type 1 and their preliminary application for humanized liver |
| topic | Liver regeneration Immunodeficiency Gene editing Disease model |
| url | https://doi.org/10.1186/s13578-022-00760-3 |
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