Abstract
Liver immunopathologic mechanisms during hepatotropic infection, malignant transformation, and autoimmunity are still unclear. Establishing a chimeric mouse with a reconstituted liver and immune system derived from a single donor across species is critical to study regional donor immune responses in recipient liver. Using a strain of mice deficient in tyrosine catabolic enzyme fumarylacetoacetate hydrolase (fah -/-) and bone marrow transplantation (BMT), we reconstituted the donor's hepatocytes and immune cells across host species barrier. Syngeneic, allogeneic or even xenogeneic rat BMT rescued most recipient fah-/- mice against liver failure by donor BM-derived FAH+ hepatocytes. Importantly, immune system developed normally in chimeras, and the immune cells together with organ architecture were intact and functional. Thus, donor BM can across host species barrier and concurrently reconstitutes MHC-identical response between immune cells and hepatocytes, giving rise to a new simple and convenient small animal model to study donor's liver immune response in mice.
Highlights
The liver diseases caused by hepatitis B virus and hepatitis C virus infection are among the most important human health problems [1]
In summary (Table 1), our major finding is that BMCs from a single individual can successfully differentiate into both immune cells and hepatocytes, and functionally repopulate the immune system and liver in irradiated fah-/- mice
It is the first mouse model with immune and liver reconstitution from a single BMC donor across the host species barrier, which was carried out by using syngeneic, allogeneic, or xenogeneic bone marrow transplanted (BMT). These findings provide a further approach for establishing a dual humanized mouse model with HLA-matched human immune cells and human hepatocytes by using a more immunodeficient fah-/- mouse, such as fah-/- NOG, in the future
Summary
The liver diseases caused by hepatitis B virus and hepatitis C virus infection are among the most important human health problems [1]. Establishing a chimeric mouse with a reconstituted liver and immune system derived from a single donor is critical to study MHC-restricted immune responses against pathogen-infected, transformed or autoimmune hepatocytes in a physiologic setting. Chimeras with donor-derived hepatocytes can be created by transplanting exogenous hepatocytes or embryonic stem cells, like in the uroplasminogenactivator (uPA) transgenic [15] or fumarylacetoacetate hydrolase (FAH)-deficient models [16] Both uPA transgenic mouse and FAH deficient mouse suffer from progressive liver failure, so that donor’s hepatocytes could engraft and repopulate in recipient mouse more . Donor BM can across host species barrier and concurrently reconstitutes MHC-identical response between immune cells and hepatocytes This method gives rise to a new simple and convenient small animal model to study donor’s liver immune response across host species barrier in mice
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