Current advances in humanized mouse models

Abstract

Humanized mouse models that have received human cells or tissue transplants are extremely useful in basic and applied human disease research. Highly immunodeficient mice, which do not reject xenografts and support cell and tissue differentiation and growth, are indispensable for generating additional appropriate models. Since the early 2000s, a series of immunodeficient mice appropriate for generating humanized mice has been successively developed by introducing the IL-2Rγ(null) gene (e.g., NOD/SCID/γc(null) and Rag2(null)γc(null) mice). These strains show not only a high rate of human cell engraftment, but also generate well-differentiated multilineage human hematopoietic cells after human hematopoietic stem cell (HSC) transplantation. These humanized mice facilitate the analysis of human hematology and immunology in vivo. However, human hematopoietic cells developed from HSCs are not always phenotypically and functionally identical to those in humans. More recently, a new series of immunodeficient mice compensates for these disadvantages. These mice were generated by genetically introducing human cytokine genes into NOD/SCID/γc(null) and Rag2(null)γc(null) mice. In this review, we describe the current knowledge of human hematopoietic cells developed in these mice. Various human disease mouse models using these humanized mice are summarized.

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Figure 1

The history of the development on immunodeficient mice for humanized mice model. In retrospect, nude mice or SCID mice were the first immunodeficient strains. Subsequently, their congenic strains were generated to improve engraftment capacities. NOD/SCID mice established in 1995 have been a milestone in this field, because of the severer phenotype than nude and SCID mice. In early 2000s, NOG, NSG and BRG mice were established by introducing the IL-2Rγnull allele into NOD/SCID or BALB/cA RAG2null mice. Due to the complete loss of murine immune systems, human hematopoiesis has been enormously enhanced in these mice. Currently, these strains were further improved by introducing human genes for various cytokines or HLA class I and II, so as to recapitulate a human bona fide hematopoiesis and immune system. The superscripts represent the respective references. BRG, BALB/cA-Rag2nullIl2rγnull; HLA, histocompatibility leukocyte antigen; NOD, nonobese diabetic; NSG, NOD/LtSz-Prkdcscid Il2rgtm1Wjl/J; SCID, severe combined immunodeficiency.