Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis
Background & Aims: Liver lobules are typically subdivided into 3 metabolic zones: zones 1, 2, and 3. However, the contribution of zonal differences in hepatocytes to liver regeneration, as well as to carcinogenic susceptibility, remains unclear. Methods: We developed a new method for sustain...
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Language: | English |
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Elsevier
2021-08-01
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Series: | JHEP Reports |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555921000914 |
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doaj-eb6538ad7f884c609ff2050f2b466934 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shigeyuki Kurosaki Hayato Nakagawa Yuki Hayata Satoshi Kawamura Yuki Matsushita Tomoharu Yamada Koji Uchino Yoku Hayakawa Nobumi Suzuki Masahiro Hata Mayo Tsuboi Hiroto Kinoshita Yasuo Tanaka Takuma Nakatsuka Yoshihiro Hirata Keisuke Tateishi Kazuhiko Koike |
spellingShingle |
Shigeyuki Kurosaki Hayato Nakagawa Yuki Hayata Satoshi Kawamura Yuki Matsushita Tomoharu Yamada Koji Uchino Yoku Hayakawa Nobumi Suzuki Masahiro Hata Mayo Tsuboi Hiroto Kinoshita Yasuo Tanaka Takuma Nakatsuka Yoshihiro Hirata Keisuke Tateishi Kazuhiko Koike Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis JHEP Reports Hepatocellular carcinoma Liver regeneration Metabolic dysfunction-associated fatty liver disease Wnt/β-catenin signal Metabolic zonation |
author_facet |
Shigeyuki Kurosaki Hayato Nakagawa Yuki Hayata Satoshi Kawamura Yuki Matsushita Tomoharu Yamada Koji Uchino Yoku Hayakawa Nobumi Suzuki Masahiro Hata Mayo Tsuboi Hiroto Kinoshita Yasuo Tanaka Takuma Nakatsuka Yoshihiro Hirata Keisuke Tateishi Kazuhiko Koike |
author_sort |
Shigeyuki Kurosaki |
title |
Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis |
title_short |
Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis |
title_full |
Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis |
title_fullStr |
Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis |
title_full_unstemmed |
Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis |
title_sort |
cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis |
publisher |
Elsevier |
series |
JHEP Reports |
issn |
2589-5559 |
publishDate |
2021-08-01 |
description |
Background & Aims: Liver lobules are typically subdivided into 3 metabolic zones: zones 1, 2, and 3. However, the contribution of zonal differences in hepatocytes to liver regeneration, as well as to carcinogenic susceptibility, remains unclear. Methods: We developed a new method for sustained genetic labelling of zone 3 hepatocytes and performed fate tracing to monitor these cells in multiple mouse liver tumour models. Results: We first examined changes in the zonal distribution of the Wnt target gene Axin2 over time using Axin2-CreERT2;Rosa26-Lox-Stop-Lox-tdTomato mice (Axin2;tdTomato). We found that following tamoxifen administration at 3 weeks of age, approximately one-third of total hepatocytes that correspond to zone 3 were labelled in Axin2;tdTomato mice; the tdTomato+ cell distribution closely matched that of the zone 3 marker CYP2E1. Cell fate analysis revealed that zone 3 hepatocytes maintained their own lineage but rarely proliferated beyond their liver zonation during homoeostasis; this indicated that our protocol enabled persistent genetic labelling of zone 3 hepatocytes. Using this system, we found that zone 3 hepatocytes generally had high neoplastic potential, which was promoted by constitutive activation of Wnt/β-catenin signalling in the pericentral area. However, the frequency of zone 3 hepatocyte-derived tumours varied depending on the regeneration pattern of the liver parenchyma in response to liver injury. Notably, Axin2-expressing hepatocytes undergoing chronic liver injury significantly contributed to liver regeneration and possessed high neoplastic potential. Additionally, we revealed that the metabolic phenotypes of liver tumours were acquired during tumorigenesis, irrespective of their spatial origin. Conclusions: Hepatocytes receiving Wnt/β-catenin signalling from their microenvironment have high neoplastic potential, and Wnt/β-catenin signalling is a potential drug target for the prevention of hepatocellular carcinoma. Lay summary: Lineage tracing revealed that zone 3 hepatocytes residing in the pericentral niche have high neoplastic potential. Under chronic liver injury, hepatocytes receiving Wnt/β-catenin signalling broadly exist across all hepatic zones and significantly contribute to liver tumorigenesis as well as liver regeneration. Wnt/β-catenin signalling is a potential drug target for the prevention of hepatocellular carcinoma. |
topic |
Hepatocellular carcinoma Liver regeneration Metabolic dysfunction-associated fatty liver disease Wnt/β-catenin signal Metabolic zonation |
url |
http://www.sciencedirect.com/science/article/pii/S2589555921000914 |
work_keys_str_mv |
AT shigeyukikurosaki cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT hayatonakagawa cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT yukihayata cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT satoshikawamura cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT yukimatsushita cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT tomoharuyamada cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT kojiuchino cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT yokuhayakawa cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT nobumisuzuki cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT masahirohata cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT mayotsuboi cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT hirotokinoshita cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT yasuotanaka cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT takumanakatsuka cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT yoshihirohirata cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT keisuketateishi cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis AT kazuhikokoike cellfateanalysisofzone3hepatocytesinliverinjuryandtumorigenesis |
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1721203713550319616 |
spelling |
doaj-eb6538ad7f884c609ff2050f2b4669342021-08-18T04:22:54ZengElsevierJHEP Reports2589-55592021-08-0134100315Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesisShigeyuki Kurosaki0Hayato Nakagawa1Yuki Hayata2Satoshi Kawamura3Yuki Matsushita4Tomoharu Yamada5Koji Uchino6Yoku Hayakawa7Nobumi Suzuki8Masahiro Hata9Mayo Tsuboi10Hiroto Kinoshita11Yasuo Tanaka12Takuma Nakatsuka13Yoshihiro Hirata14Keisuke Tateishi15Kazuhiko Koike16Department of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, Japan; Corresponding author. Address: Department of Gastroenterology, The University of Tokyo, 7-3-1 Bunkyo-ku Hongo, Tokyo 113-8655, Japan. Tel.: +81-3-3815-5411; Fax: +81-3-3814-0021Department of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDivision of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDivision of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanDepartment of Gastroenterology, The University of Tokyo, Tokyo, JapanBackground & Aims: Liver lobules are typically subdivided into 3 metabolic zones: zones 1, 2, and 3. However, the contribution of zonal differences in hepatocytes to liver regeneration, as well as to carcinogenic susceptibility, remains unclear. Methods: We developed a new method for sustained genetic labelling of zone 3 hepatocytes and performed fate tracing to monitor these cells in multiple mouse liver tumour models. Results: We first examined changes in the zonal distribution of the Wnt target gene Axin2 over time using Axin2-CreERT2;Rosa26-Lox-Stop-Lox-tdTomato mice (Axin2;tdTomato). We found that following tamoxifen administration at 3 weeks of age, approximately one-third of total hepatocytes that correspond to zone 3 were labelled in Axin2;tdTomato mice; the tdTomato+ cell distribution closely matched that of the zone 3 marker CYP2E1. Cell fate analysis revealed that zone 3 hepatocytes maintained their own lineage but rarely proliferated beyond their liver zonation during homoeostasis; this indicated that our protocol enabled persistent genetic labelling of zone 3 hepatocytes. Using this system, we found that zone 3 hepatocytes generally had high neoplastic potential, which was promoted by constitutive activation of Wnt/β-catenin signalling in the pericentral area. However, the frequency of zone 3 hepatocyte-derived tumours varied depending on the regeneration pattern of the liver parenchyma in response to liver injury. Notably, Axin2-expressing hepatocytes undergoing chronic liver injury significantly contributed to liver regeneration and possessed high neoplastic potential. Additionally, we revealed that the metabolic phenotypes of liver tumours were acquired during tumorigenesis, irrespective of their spatial origin. Conclusions: Hepatocytes receiving Wnt/β-catenin signalling from their microenvironment have high neoplastic potential, and Wnt/β-catenin signalling is a potential drug target for the prevention of hepatocellular carcinoma. Lay summary: Lineage tracing revealed that zone 3 hepatocytes residing in the pericentral niche have high neoplastic potential. Under chronic liver injury, hepatocytes receiving Wnt/β-catenin signalling broadly exist across all hepatic zones and significantly contribute to liver tumorigenesis as well as liver regeneration. Wnt/β-catenin signalling is a potential drug target for the prevention of hepatocellular carcinoma.http://www.sciencedirect.com/science/article/pii/S2589555921000914Hepatocellular carcinomaLiver regenerationMetabolic dysfunction-associated fatty liver diseaseWnt/β-catenin signalMetabolic zonation |