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A humanized mouse model of liver fibrosis following expansion of transplanted hepatic stellate cells

Laboratory Investigationvolume 98pages525536 (2018) | Download Citation

Abstract

Hepatic stellate cells (HSCs) are major contributors to liver fibrosis, as hepatic injuries may cause their transdifferentiation into myofibroblast-like cells capable of producing excessive extracellular matrix proteins. Also, HSCs can modulate engraftment of transplanted hepatocytes and contribute to liver regeneration. Therefore, understanding the biology of human HSCs (hHSCs) is important, but effective methods have not been available to address their fate in vivo. To investigate whether HSCs could engraft and repopulate the liver, we transplanted GFP-transduced immortalized hHSCs into immunodeficient NOD/SCID mice. Biodistribution analysis with radiolabeled hHSCs showed that after intrasplenic injection, the majority of transplanted cells rapidly translocated to the liver. GFP-immunohistochemistry demonstrated that transplanted hHSCs engrafted alongside hepatic sinusoids. Prior permeabilization of the sinusoidal endothelial layer with monocrotaline enhanced engraftment of hHSCs. Transplanted hHSCs remained engrafted without relevant proliferation in the healthy liver. However, after CCl4 or bile duct ligation-induced liver damage, transplanted hHSCs expanded and contributed to extracellular matrix production, formation of bridging cell-septae and cirrhosis-like hepatic pseudolobules. CCl4-induced injury recruited hHSCs mainly to zone 3, whereas after bile duct ligation, hHSCs were mainly in zone 1 of the liver lobule. Transplanted hHSCs neither transdifferentiated into other cell types nor formed tumors in these settings. In conclusion, a humanized mouse model was generated by transplanting hHSCs, which proliferated during hepatic injury and inflammation, and contributed to liver fibrosis. The ability to repopulate the liver with transplanted hHSCs will be particularly significant for mechanistic studies of cell-cell interactions and fibrogenesis within the liver.

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Additional information

Daniel Benten and Johannes Kluwe contributed equally to this work.

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Acknowledgements

This work was supported in part by NIH grants R01 DK071111 and P30-DK41296. DB received support from Deutsche Forschungsgemeinschaft, grants BE 2559/2–1 and BE 2559/2–2 and SFB 841. JK received support from the Deutsche Forschungsgemeinschaft, grant KL2140/2–1 and SFB 841. JK and DB received support from Forschungsförderungsfonds Medizin, Hamburg University.

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Author notes

    Affiliations

    1. Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY, USA

      • Daniel Benten
      •  & Sanjeev Gupta
    2. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

      • Daniel Benten
      • , Johannes Kluwe
      • , Jan W. Wirth
      • , Nina D. Thiele
      • , Michael Koepke
      • , Reni Tjandra
      • , Tassilo Volz
      •  & Marc Lutgehetmann
    3. Helios Klinikum Duisburg, Duisburg, Germany

      • Daniel Benten
    4. Department of HealthSciences, Università del Piemonte Orientale “A. Avogadro”, Novara, Italy

      • Antonia Follenzi
    5. Division of Nuclear Medicine and Molecular Imaging, Long Island Jewish Health Center, NorthWell Health, New Hyde Park, NY, USA

      • Kuldeep K. Bhargava
      •  & Christopher J. Palestro

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    The authors declare that they have no conflict of interest.

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    Correspondence to Daniel Benten or Sanjeev Gupta.

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    DOI

    https://doi.org/10.1038/s41374-017-0010-7