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Cited by 87Xenotransplantation and immune responseHepatitis B Virus StudiesLiver physiology and pathology

Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells

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Billerbeck, Eva, Mommersteeg, Michiel C., Shlomai, Amir, Xiao, Jing W., Andrus, Linda, Bhatta, Ankit, Vercauteren, Koen, Michailidis, Eleftherios +6 more·2016·Journal of Hepatology
DOI 10.1016/j.jhep.2016.04.022PMC PMC4955758
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Abstract

Background & aims Human liver chimeric mice are useful models of human hepatitis virus infection, including hepatitis B and C virus infections. Independently, immunodeficient mice reconstituted with CD34(+) hematopoietic stem cells (HSC) derived from fetal liver reliably develop human T and B lymphocytes. Combining these systems has long been hampered by inefficient liver reconstitution of human fetal hepatoblasts. Our study aimed to enhance hepatoblast engraftment in order to create a mouse model with syngeneic human liver and immune cells. Methods The effects of human oncostatin-M administration on fetal hepatoblast engraftment into immunodeficient fah(-/-) mice was tested. Mice were then transplanted with syngeneic human hepatoblasts and HSC after which human leukocyte chimerism and functionality were analyzed by flow cytometry, and mice were challenged with HBV. Results Addition of human oncostatin-M enhanced human hepatoblast engraftment in immunodeficient fah(-/-) mice by 5-100 fold. In contrast to mice singly engrafted with HSC, which predominantly developed human T and B lymphocytes, mice co-transplanted with syngeneic hepatoblasts also contained physiological levels of human monocytes and natural killer cells. Upon infection with HBV, these mice displayed rapid and sustained viremia. Conclusions Our study provides a new mouse model with improved human fetal hepatoblast engraftment and an expanded human immune cell repertoire. With further improvements, this model may become useful for studying human immunity against viral hepatitis. Lay summary Important human pathogens such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus only infect human cells which complicates the development of mouse models for the study of these pathogens. One way to make mice permissive for human pathogens is the transplantation of human cells into immune-compromised mice. For instance, the transplantation of human liver cells will allow the infection of these so-called "liver chimeric mice" with hepatitis B virus and hepatitis C virus. The co-transplantation of human immune cells into liver chimeric mice will further allow the study of human immune responses to hepatitis B virus or hepatitis C virus. However, for immunological studies it will be crucial that the transplanted human liver and immune cells are derived from the same human donor. In our study we describe the efficient engraftment of human fetal liver cells and immune cells derived from the same donor into mice. We show that liver co-engraftment resulted in an expanded human immune cell repertoire, including monocytes and natural killer cells in the liver. We further demonstrate that these mice could be infected with hepatitis B virus, which lead to an expansion of natural killer cells. In conclusion we have developed a new mouse model that could be useful to study human immune responses to human liver pathogens.

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  • For hepatocytes to survive in chimeric liver mice, some level of immunodeficiency must be induced to avoid rejection; this feature could potentially be circumvented with bone marrow ablation and injection of human immune cells.

    “For the hepatocytes to survive, however, some level of immunodeficiency must be induced to avoid rejection; a feature which could potentially be circumvented with bone marrow ablation and injection of human immune cells(55).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [55]

    The Introduction says recipient mice are immunodeficient to prevent rejection of human cells. Materials and methods describes irradiating immunodeficient mice and transplanting human hepatoblasts with human hematopoietic stem cells, which supports the proposed route to adding human immune cells. It does not describe bone marrow ablation or show that the mice’s underlying immunodeficiency was eliminated; the Discussion says their human immune system was not fully functional. (LLM, conf=0.84)

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  • Reduced numbers of each major circulating lymphocyte subset, T, B and NK cells, are observed in heavy drinkers.

    “Reduced numbers of each major circulating lymphocyte subset (T, B and NK cells) is observed in heavy drinkers (55), while mice exposed to ethanol exhibit an imbalance between the naive and memory compartments of their CD4+ T cells due to increased homeostatic proliferation of memory cells (56, 57).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [55]

    The Results sections on immune-cell reconstitution and early HBV infection discuss T, B and NK cells in humanized mice, but not lymphocyte counts in heavy drinkers. Searches for heavy drinking, alcohol and ethanol found no passage addressing the attributed claim; page numbers were not available in our copy. (LLM, conf=0.76)

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Authors
Billerbeck, E., Mommersteeg, M. C., Shlomai, A., Xiao, J. W., Andrus, L., Bhatta, A., Vercauteren, K., Michailidis, E., Dorner, M., Krishnan, A., Charlton, M. R., Chiriboga, L., Rice, C. M., & de Jong, Y. P.
Affiliations
  • Rockefeller University (US)
  • Imperial College London (GB)
  • Mayo Clinic (US)
  • NYU Langone Health (US)
Corresponding author
Rice, Charles M.
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2016-08
Volume
65
Issue
2
Pages
334-343
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2016.04.022
PMC
PMC4955758
OpenAlex
W2345764800
Cited by
87
References
2
Citations by year
2026: 7 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 14 · 2019: 9 · 2018: 10 · 2017: 14 · 2016: 3
FWCI
13.29
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
Funders
  • National Cancer Institute (P30CA016087)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK085713, K08DK090576)
Topics
  • Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
  • Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
oncostatin M, monocytes, natural killer cells, hepatitis B virus, hepatitis C virus, humanized mice, CD34+ hematopoietic stem cells, viremia
MeSH terms
Animals, Hepatitis B, Humans, Killer Cells, Natural, Monocytes, Mice, SCID, Hepatocytes, Mice

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