Figure 1. Creation and future improvements of human liver–chimeric FRG mice.

In the model described in the current issue by Bissig et al. (16), enclosed in the shaded rectangle, hepatocytes are isolated from adult human liver tissue and injected into FRG mice that are cycled off the protective drug NTBC. Human hepatocyte engraftment levels are then monitored by serial human albumin (hAlb) measurements in the serum of transplanted mice. Over 2–3 months, the human hepatocytes expand and can repopulate up to 97% of the FRG mouse liver, with the remainder of liver-resident cells likely of murine origin. This robust system can be used to study HBV and HCV infections in vivo and can serve as a scaffold for more complex humanized mouse models. The engrafted FRG mice reported by Bissig et al. could potentially be combined with mice bred to posses a human immune system, which are generated by transplantation of human CD34⁺ stem cells (HSCs) (23). Use of donor hepatocytes and HSCs derived from fetal liver may allow FRG mice animals to be repopulated with the immune system and liver tissue of an individual human donor, facilitating studies of immunopathogenesis and vaccine testing. Another use for the FRG model will be to study hepatocyte differentiation from human induced pluripotent stem (iPS) cells (24, 25) derived from dermal fibroblasts or from embryonic stem cells (26). Steps depicted by solid lines are currently feasible; the dashed lines refer to steps that are under investigation but have not yet proven workable. Figure modified with permission from Hepatology (27), Nature Reviews Immunology (28), and Cell Host & Microbe (22) and based on concepts discussed in ref. 29.