title: Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Billerbeck
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
authors.forename: Michiel C
authors.initials: MC
authors.lastname: Mommersteeg
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Shlomai
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
authors.forename: Jing W
authors.initials: JW
authors.lastname: Xiao
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Andrus
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Bhatta
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
authors.forename: Koen
authors.initials: K
authors.lastname: Vercauteren
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
authors.forename: Eleftherios
authors.initials: E
authors.lastname: Michailidis
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA; Present address: Section of Virology and Section of Hepatology, Imperial College London, London, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dorner
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Charlton
authors.affiliation: Department of Pathology, New York University Medical Center, New York, NY, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Chiriboga
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. Electronic address: ricec@rockefeller.edu.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA. Electronic address: ydj2001@med.cornell.edu.
authors.forename: Ype P
authors.initials: YP
authors.lastname: de Jong
mesh_terms: D000818:Animals; D006509:Hepatitis B; D022781:Hepatocytes; D006801:Humans; D007694:Killer Cells, Natural; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes
keywords: Hepatitis B virus; Human immune cells; Liver chimeric mice; Xenotransplantation