Disruption of the transcription factor recombination signal-binding protein-Jκ (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice

Authors

  • Lin Wang,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
    2. Department of Hepatic Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
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    • These authors contributed equally to this study.

  • Chun-Mei Wang,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
    2. National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, China
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    • These authors contributed equally to this study.

  • Li-Hong Hou,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
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    • These authors contributed equally to this study.

  • Guo-Rui Dou,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
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    • These authors contributed equally to this study.

  • Yao-Chun Wang,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
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  • Xing-Bin Hu,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
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  • Fei He,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
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  • Fan Feng,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
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  • Hong-Wei Zhang,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
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  • Ying-Min Liang,

    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
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  • Ke-Feng Dou,

    Corresponding author
    1. Department of Hepatic Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
    • Department of Hepatic Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an 710032, China
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    • fax: (86)-29-83246270

  • Hua Han

    Corresponding author
    1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China
    • Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China
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    • fax: (86)-29-83246270


  • Potential conflict of interest: Nothing to report.

Abstract

Liver sinusoid (LS) endothelial cells (LSECs) support hepatocytes in resting livers and proliferate during liver regeneration to revascularize regenerated liver parenchyma. We report that recombination signal-binding protein-Jκ (RBP-J), the critical transcription factor mediating Notch signaling, regulates both resting and regenerating LSECs. Conditional deletion of RBP-J resulted in LSEC proliferation and a veno-occlusive disease–like phenotype in the liver, as manifested by liver congestion, deposition of fibrin-like materials in LSs, edema in the space of Disse, and increased apoptosis of hepatocytes. Regeneration of liver was remarkably impaired, with reduced LSEC proliferation and destroyed sinusoidal structure. LSEC degeneration was obvious in the regenerating liver of RBP-J–deficient mice, with some LSECs losing cytoplasm, and organelles protruding into the remnant plasma-membrane of LSs to hamper the microcirculation and intensify veno-occlusive disease during liver regeneration. Hepatocytes were also degenerative, as shown by dilated endoplasmic reticulum, decreased proliferation, and increased apoptosis during liver regeneration. Molecular analyses revealed that the dynamic expression of several related molecules—such as vascular endothelial growth factor, vascular endothelial growth factor receptors 1 and 2, interleukin-6, and hepatocyte growth factor—was disturbed. Conclusion: Notch/RBP-J signaling may play dual roles in LSECs: in resting liver it represses proliferation, and in regenerating liver it supports proliferation and functional differentiation. (HEPATOLOGY 2009;49:268-277.)

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