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Cell Death Dis. 2018 May 1;9(5):575. doi: 10.1038/s41419-018-0622-x.

The extent of liver injury determines hepatocyte fate toward senescence or cancer.

Author information

1
Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, 200433, Shanghai, China.
2
Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 200123, Shanghai, China.
3
School of Medicine, Tongji University, 200092, Shanghai, China.
4
School of Medicine, Yunnan University, 650091, Kunming, Yunnan, China.
5
Naval Medicine Research Institute, Second Military Medical University, 200433, Shanghai, China.
6
The Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, 010070, Huhhot, China.
7
Department of Hepatology, Shanghai East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China.
8
Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
9
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
10
Hepatoscience Incorporation, 725 San Aleso Ave, Sunnyvale, CA, 94085, USA.
11
Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 200123, Shanghai, China. liu.zhongmin@tongji.edu.cn.
12
Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, 200433, Shanghai, China. zyhe@tongji.edu.cn.
13
Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 200123, Shanghai, China. zyhe@tongji.edu.cn.

Abstract

It is well known that induction of hepatocyte senescence could inhibit the development of hepatocellular carcinoma (HCC). Until now, it is still unclear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury, on the contrary did not result into hepatocyte senescence, but led to a significant incidence of HCC instead. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. Meanwhile, immune surveillance, especially the activations of macrophages, was activated after re-induction of senescence by severe acute liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with activating immune surveillance and a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC.

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