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

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.

Recapitulation of treatment response patterns in a novel humanized mouse model for chronic hepatitis B virus infection

“…We have shown here that FAH Δexon9 NRG mice, similar to immunodeficient FAH Δexon5 mice, are susceptible to HBV infection once engrafted with human hepatocytes (Billerbeck et al, 2016; Bissig et al, 2010). All viral intermediates can be observed in these mice, including HbsAg in serum, HBcAg-positive human hepatocytes, HBV total DNA in serum and liver, HBV pgRNA and HBV cccDNA.…”

“…These mouse models have been utilized to investigate HBV or HCV pathogenesis and the host immune response to infection (Bility et al, 2014; Billerbeck et al, 2016; Strick-Marchand et al, 2015; Washburn et al, 2011). The NOD Rag1−/− IL2Rγ NULL background is amenable to human hematopoietic stem cell engraftment (Brehm et al, 2010; Pearson et al, 2008).…”

“…FRG and FNRG highly engrafted with human hepatocytes can sustain persistent HBV (Billerbeck et al, 2016; Bissig et al, 2010) and HCV infections (Bissig et al, 2010; de Jong et al, 2014). A considerable challenge in refining existing and developing new xenorecipient models is performing genetic modifications on previously characterized complex genetic backgrounds.…”

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

“…23 However, the ADCC function of MBS301 can be observed in the humanized mice (hu-CD34 NSG mice) study (Figure 7c); there was a slight visible difference between the MBS301 and MBS301 + F groups in tumor inhibition and the recurrence ratio of MBS301 was lower than that of MBS301 + F. 24 Still, the content of humanized NK cells was much lower in hu-CD34 NSG mice than in human. 25 The NK cells could account for 5–20% in human peripheral blood mononuclear cells; thus, significant ADCC function for killing cancer cells could be observed for MBS301 when used as a treatment in humans.…”

Metalloproteinases in liver fibrosis: current insights

“…Finally, humanized mice with human immune system and hepatocytes is the only model, which upon infection triggers responses similar to humans, i.e., hepatitis and fibrosis. [44][45][46][47] Genetically modified mice Genetically modified animals are becoming a more frequent tool to study liver pathophysiology as well as the roles of metalloproteinases. The liver consists of several cell types and it is not easy to target them specifically.…”