Reversal of hepatocyte senescence after continuous in vivo cell proliferation

Authors

  • Min-Jun Wang,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
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    • These authors contributed equally to this work.

  • Fei Chen,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
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    • These authors contributed equally to this work.

  • Jian-Xiu Li,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
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  • Chang-Cheng Liu,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
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  • Hai-Bin Zhang,

    1. Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China
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  • Yong Xia,

    1. Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China
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  • Bing Yu,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
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  • Pu You,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
    Current affiliation:
    1. Naval Medical Research Institute, Shanghai, P.R. China
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  • Dao Xiang,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
    Current affiliation:
    1. Naval Medical Research Institute, Shanghai, P.R. China
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  • Lian Lu,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
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  • Hao Yao,

    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
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  • Uyunbilig Borjigin,

    1. Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot, P.R. China
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  • Guang-Shun Yang,

    1. Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China
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  • Kirk J. Wangensteen,

    1. Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
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  • Zhi-Ying He,

    Corresponding author
    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
    • Address reprint requests to: Yiping Hu, Ph.D., Zhiying He, Ph.D., Department of Cell Biology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, P.R. China. E-mail: yphu@smmu.edu.cn, zyhe@smmu.edu.cn; fax: +86-21-8187-0948; or Xin Wang, Ph.D., Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot010021, P.R. China. E-mail: wangxin_cn@imu.edu.cn; fax: +86-0471-4994-329.

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  • Xin Wang,

    Corresponding author
    1. Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot, P.R. China
    2. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
    3. Hepatoscience Inc, Palo Alto, CA, USA
    • Address reprint requests to: Yiping Hu, Ph.D., Zhiying He, Ph.D., Department of Cell Biology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, P.R. China. E-mail: yphu@smmu.edu.cn, zyhe@smmu.edu.cn; fax: +86-21-8187-0948; or Xin Wang, Ph.D., Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot010021, P.R. China. E-mail: wangxin_cn@imu.edu.cn; fax: +86-0471-4994-329.

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  • Yi-Ping Hu

    Corresponding author
    1. Department of Cell Biology, Second Military Medical University, Shanghai, P.R. China
    2. Center for Stem Cell and Medicine, Graduate School, Second Military Medical University, Shanghai, P.R. China
    • Address reprint requests to: Yiping Hu, Ph.D., Zhiying He, Ph.D., Department of Cell Biology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, P.R. China. E-mail: yphu@smmu.edu.cn, zyhe@smmu.edu.cn; fax: +86-21-8187-0948; or Xin Wang, Ph.D., Key Laboratory of National Education Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot010021, P.R. China. E-mail: wangxin_cn@imu.edu.cn; fax: +86-0471-4994-329.

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  • Funded by National Key Basic Research and Development Program of China (2011CB966200, 2010CB945600), National Natural Science Foundation of China (31271474, 31171309, 30971462, 31271469, 31271042, and 31100996).

  • Potential conflict of interest: Nothing to report.

Abstract

A better understanding of hepatocyte senescence could be used to treat age-dependent disease processes of the liver. Whether continuously proliferating hepatocytes could avoid or reverse senescence has not yet been fully elucidated. We confirmed that the livers of aged mice accumulated senescent and polyploid hepatocytes, which is associated with accumulation of DNA damage and activation of p53-p21 and p16ink4a-pRB pathways. Induction of multiple rounds continuous cell division is hard to apply in any animal model. Taking advantage of serial hepatocyte transplantation assays in the fumarylacetoacetate hydrolase-deficient (Fah−/−) mouse, we studied the senescence of hepatocytes that had undergone continuous cell proliferation over a long time period, up to 12 rounds of serial transplantations. We demonstrated that the continuously proliferating hepatocytes avoided senescence and always maintained a youthful state. The reactivation of telomerase in hepatocytes after serial transplantation correlated with reversal of senescence. Moreover, senescent hepatocytes harvested from aged mice became rejuvenated upon serial transplantation, with full restoration of proliferative capacity. The same findings were also true for human hepatocytes. After serial transplantation, the high initial proportion of octoploid hepatocytes decreased to match the low level of youthful liver. Conclusion: These findings suggest that the hepatocyte “ploidy conveyer” is regulated differently during aging and regeneration. The findings of reversal of hepatocyte senescence could enable future studies on liver aging and cell therapy. (Hepatology 2014;60:349–361)

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