Differentiate into not only immune cells but also hepatocytes, which greatly helps understanding the maturation of donor immune system, and virusinfected donor hepatocytes, respectively; however, from our knowledge, no experiment was practically economically carried out to exhibit the donor immune response against their own hepatocyte-presented antigens because lacking chimeras mouse with a MHC-matched response between immune cells and hepatocytes which needs a dual reconstitution from a single donor. Chimeras with donor-derived hepatocytes can also be created by transplanting exogenous hepatocytes or embryonic stem cells, like in the uroplasminogenactivator transgenic or fumarylacetoacetate hydrolase -deficient models. 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 easily. However, neither the immune- nor liverreconstituted chimera alone is sufficient to further evaluate the interaction between the immune system and the pathogen-infected or inflamed liver organs. There is a significant need for a model system, with MHCidentity between donor immune cells and pathogen-targeting organs, to further investigate the pathology, immune correlates, and mechanisms of highly specialized pathogens like HBV, HCV and malaria. To avoid the potential complication from histocompatibility, hematopoietic and hepatic progenitors had better to be from the same donor. It was recently reported that HSC may also differentiate into hepatocytes in bone marrow transplanted mice. We therefore hypothesized that donor HSCs may BAY-60-7550 concurrently differentiate into immune cells and hepatocytes in recipients that have open tissue space, which will greatly benefit exploiting the donor’s MHC-restricted interaction between immune cells and hepatocytes. Here, using fah-deficient mice and BMT, we reconstituted donor hepatocytes and immune cells across host species barrier. All recipient fah-/- mice survived without NTBC feeding at least 5 months after syn-, allo- and xeno- BMT, and donor BMderived hepatocytes were detected in liver sections. Importantly, donor immune systems developed normally in MHC-identical 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. Thus, 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. Development of humanized mice provides insights into in vivo human biology, which would otherwise be severely limited by ethical and/or technical constraints. Human immune system mice are already established, showing a potential as the available model for the study of human immune response and human lymphotropic pathogens in mice.