Loss of hepatocyte cell division leads to liver inflammation and fibrosis
Dewhurst, Matthew R ; Ow, Jin Rong ; Zafer, Gözde ; van Hul, Noémi K M ; Wollmann, Heike ; Bisteau, Xavier ; Brough, David ; Choi, Hyungwon and Kaldis, Philipp LU
(2020)
In PLoS Genetics
16(11).
p.1009084-1009084
- Abstract
The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and... (More)
The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1Liv-/- mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.
(Less)
- author
- Dewhurst, Matthew R
; Ow, Jin Rong
; Zafer, Gözde
; van Hul, Noémi K M
; Wollmann, Heike
; Bisteau, Xavier
; Brough, David
; Choi, Hyungwon
and Kaldis, Philipp
LU
- organization
- publishing date
- 2020-11-04
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS Genetics
- volume
- 16
- issue
- 11
- pages
- 1009084 - 1009084
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- pmid:33147210
- scopus:85095675990
- ISSN
- 1553-7404
- DOI
- 10.1371/journal.pgen.1009084
- language
- English
- LU publication?
- yes
- id
- a0dc4d05-671e-426e-b6f1-a94fd5e63a48
- date added to LUP
- 2020-11-09 09:10:59
- date last changed
- 2024-06-14 01:58:21
@article{a0dc4d05-671e-426e-b6f1-a94fd5e63a48,
abstract = {{<p>The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1Liv-/- mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.</p>}},
author = {{Dewhurst, Matthew R and Ow, Jin Rong and Zafer, Gözde and van Hul, Noémi K M and Wollmann, Heike and Bisteau, Xavier and Brough, David and Choi, Hyungwon and Kaldis, Philipp}},
issn = {{1553-7404}},
language = {{eng}},
month = {{11}},
number = {{11}},
pages = {{1009084--1009084}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS Genetics}},
title = {{Loss of hepatocyte cell division leads to liver inflammation and fibrosis}},
url = {{http://dx.doi.org/10.1371/journal.pgen.1009084}},
doi = {{10.1371/journal.pgen.1009084}},
volume = {{16}},
year = {{2020}},
}