Hepatic loss of survivin impairs postnatal liver development and promotes expansion of hepatic progenitor cells in mice

Authors

  • Dan Li,

    1. Graduate University of Chinese Academy of Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    2. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Jin Cen,

    1. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Xiaotao Chen,

    1. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Edward M. Conway,

    1. Center for Blood Research, Division of Hematology-Oncology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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  • Yuan Ji,

    1. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
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  • Lijian Hui

    Corresponding author
    1. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    • Address reprint requests to: Lijian Hui, Ph.D., State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, 200031 Shanghai, China. E-mail: ljhui@sibcb.ac.cn; fax: +86-21-5492132.

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  • Potential conflict of interest: Nothing to report.

  • L.H.'s laboratory is funded by the National Science Foundation of China (31071238), the Ministry of Science and Technology of China (2012CB945001 and 2011ZX09307-302-01), and the Chinese Academy of Sciences (the Hundred Talents Program). E.M.C. is supported by the Canadian Institutes for Health Research, the Canada Foundations for Innovation, and the Natural Sciences and Engineering Research Council of Canada. E.M.C. holds a CSL-Behring Research Chair and a Canada Research Chair in Endothelial Cell Biology and is an adjunct scientist with the Canadian Blood Services (CBS). The authors thank Dr. V. Factor (National Cancer Institute, National Institutes of Health, Bethesda, MD) for A6 antibody and Dr. X. Wang (Inner Mongolia University, Inner Mongolia, China) for antibodies against CK19.

Abstract

Hepatocytes possess a remarkable capacity to regenerate and reconstitute the parenchyma after liver damage. However, in the case of chronic injury, their proliferative potential is impaired and hepatic progenitor cells (HPCs) are activated, resulting in a ductular reaction known as oval cell response. Proapoptotic and survival signals maintain a precise balance to spare hepatocytes and progenitors from hyperplasia and cell death during regeneration. Survivin, a member of the family of inhibitor of apoptosis proteins (IAPs), plays key roles in the proliferation and apoptosis of various cell types. Here, we characterized the in vivo function of Survivin in regulating postnatal liver development and homeostasis using mice carrying conditional Survivin alleles. Hepatic perinatal loss of Survivin causes impaired mitosis, increased genome ploidy, and enlarged cell size in postnatal livers, which eventually leads to hepatocyte apoptosis and triggers tissue damage and inflammation. Subsequently, HPCs that retain genomic Survivin alleles are activated, which finally differentiate into hepatocytes and reconstitute the whole liver. By contrast, inducible ablation of Survivin in adult hepatocytes does not affect HPC activation and liver homeostasis during a long-life period. Conclusion: Perinatal Survivin deletion impairs hepatic mitosis in postnatal liver development, which induces HPC activation and reconstitution in the liver, therefore providing a novel HPC induction model. (Hepatology 2013; 58:2109–2121)

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