Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity But Develop Fewer Hepatocellular Carcinomas Following Chronic Liver Injury.
Animals
Carbon Tetrachloride
/ toxicity
Carcinoma, Hepatocellular
/ chemically induced
Cells, Cultured
Chemical and Drug Induced Liver Injury
/ etiology
Diethylnitrosamine
/ toxicity
Female
Gene Knockdown Techniques
Hepatectomy
Hepatocytes
/ drug effects
Humans
Liver
/ cytology
Liver Cirrhosis
/ genetics
Liver Neoplasms
/ chemically induced
Liver Neoplasms, Experimental
/ chemically induced
Liver Regeneration
/ drug effects
Male
Mice
Mice, Transgenic
Microfilament Proteins
/ genetics
Polyploidy
Primary Cell Culture
Protective Factors
RNA-Seq
Exome Sequencing
Cell Division
DEN
HCC
Mouse Model
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
24
08
2019
revised:
24
12
2019
accepted:
02
01
2020
pubmed:
24
1
2020
medline:
21
10
2020
entrez:
24
1
2020
Statut:
ppublish
Résumé
Thirty to 90% of hepatocytes contain whole-genome duplications, but little is known about the fates or functions of these polyploid cells or how they affect development of liver disease. We investigated the effects of continuous proliferative pressure, observed in chronically damaged liver tissues, on polyploid cells. We studied Rosa-rtTa mice (controls) and Rosa-rtTa;TRE-short hairpin RNA mice, which have reversible knockdown of anillin, actin binding protein (ANLN). Transient administration of doxycycline increases the frequency and degree of hepatocyte polyploidy without permanently altering levels of ANLN. Mice were then given diethylnitrosamine and carbon tetrachloride (CCl Liver tissues from control mice given CCl Mice with increased polyploid hepatocytes develop fewer liver tumors following chronic liver damage. Remarkably, polyploid hepatocytes maintain the ability to regenerate liver tissues during chronic damage without generating mitotic errors, and aneuploidy is not commonly observed in cirrhotic livers. Strategies to increase numbers of polypoid hepatocytes might be effective in preventing liver cancer.
Sections du résumé
BACKGROUND & AIMS
Thirty to 90% of hepatocytes contain whole-genome duplications, but little is known about the fates or functions of these polyploid cells or how they affect development of liver disease. We investigated the effects of continuous proliferative pressure, observed in chronically damaged liver tissues, on polyploid cells.
METHODS
We studied Rosa-rtTa mice (controls) and Rosa-rtTa;TRE-short hairpin RNA mice, which have reversible knockdown of anillin, actin binding protein (ANLN). Transient administration of doxycycline increases the frequency and degree of hepatocyte polyploidy without permanently altering levels of ANLN. Mice were then given diethylnitrosamine and carbon tetrachloride (CCl
RESULTS
Liver tissues from control mice given CCl
CONCLUSIONS
Mice with increased polyploid hepatocytes develop fewer liver tumors following chronic liver damage. Remarkably, polyploid hepatocytes maintain the ability to regenerate liver tissues during chronic damage without generating mitotic errors, and aneuploidy is not commonly observed in cirrhotic livers. Strategies to increase numbers of polypoid hepatocytes might be effective in preventing liver cancer.
Identifiants
pubmed: 31972235
pii: S0016-5085(20)30116-5
doi: 10.1053/j.gastro.2020.01.026
pmc: PMC8902703
mid: NIHMS1569257
pii:
doi:
Substances chimiques
Anln protein, mouse
0
Microfilament Proteins
0
Diethylnitrosamine
3IQ78TTX1A
Carbon Tetrachloride
CL2T97X0V0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1698-1712.e14Subventions
Organisme : NCI NIH HHS
ID : R01 CA233794
Pays : United States
Organisme : NIEHS NIH HHS
ID : R03 ES026397
Pays : United States
Informations de copyright
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
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