Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis

Autor: Yuki Matsushita, Hiroto Kinoshita, Keisuke Tateishi, Masahiro Hata, Nobumi Suzuki, Koji Uchino, Kazuhiko Koike, Hayato Nakagawa, Satoshi Kawamura, Yoshihiro Hirata, Tomoharu Yamada, Yuki Hayata, Mayo Tsuboi, Yoku Hayakawa, Takuma Nakatsuka, Shigeyuki Kurosaki, Yasuo Tanaka
Jazyk: angličtina
Rok vydání: 2021
Předmět:
HFD
high-fat diet
Metabolic dysfunction-associated fatty liver disease
Normal diet
Hepatocellular carcinoma
PV
perivenous
PIK3CATg
hepatocyte-specific transgenic mice harbouring mutant PIK3CA variant
RC799-869
Biology
medicine.disease_cause
GS
glutamine synthetase
RFP
red fluorescent protein
Internal Medicine
medicine
AXIN2
MAFLD
metabolic dysfunction-associated fatty liver disease
Immunology and Allergy
IF
immunofluorescence
Lobules of liver
TUNEL
terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling
MUP
major urinary protein
Liver injury
CDAHFD
choline-deficient l-amino acid-defined
high-fat diet
PP
periportal
Hepatology
ND
normal diet
Regeneration (biology)
HAL
histidine ammonia lyase
Gastroenterology
Wnt signaling pathway
CYP2E1
cytochrome P450 subfamily 2E1
Diseases of the digestive system. Gastroenterology
medicine.disease
WT
wild-type
Liver regeneration
CPS1
carbamoyl phosphate synthetase 1
Wnt/β-catenin signal
Cancer research
HCC
hepatocellular carcinoma
Carcinogenesis
Metabolic zonation
ISH
in situ hybridisation
TAM
tamoxifen
Research Article
DEN
diethylnitrosamine
Zdroj: JHEP Reports, Vol 3, Iss 4, Pp 100315-(2021)
JHEP Reports
ISSN: 2589-5559
Popis: 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.
Graphical abstract
Highlights • We developed a new method for sustained genetic labelling of Zone 3 hepatocytes. • Lineage tracing revealed that Zone 3 hepatocytes generally have high neoplastic potential. • The frequency of Zone 3 hepatocyte-derived tumours varied depending on the regeneration pattern of liver parenchyma. • Under chronic liver injury, hepatocytes receiving Wnt/β-catenin signalling significantly contributed to tumorigenesis. • Wnt/β-catenin signalling is a potential drug target for the prevention of HCC.
Databáze: OpenAIRE
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