This content is available for informational purposes, intended for those who are interested in working with mouse models to further their research.
With the advancement of modern techniques and technologies used for genetic manipulation, humanized mice have become an important asset in the field of genetic research. These mice are used to mimic human conditions and apply potential therapies more efficiently, without any of the risks involved with using human patients. The following discusses the various types of humanized mice and why they are so widely used by researchers worldwide.
What are humanized mice? To put it simply, they are animal models used as a type of surrogate of various parts of human biology, such as the human immune system. Some humanized mice may only have human cells, while others might share many genetic and physiologic properties with humans. Because the mouse genome is close in similarity to that of humans, there are many components of mouse biology and genetics that can easily be manipulated to faithfully mimic human biological qualities.
When using humanized mice in scientific research, there is no universal method or technology when it comes to how to generate humanized mice. Basically, there are three main model types to choose from: tumor, immune system, and gene targeted.
In the case of a tumor model, immunodeficient mice, or mice lacking a mouse immune system, can be transplanted with human tumor cells or tissue. Scientists will utilize this type of mouse model in order to study a wide variety of conditions and diseases in vivo.
Immunodeficient mouse models are used for a variety of applications in biomedical research. Whether researchers are grafting human tumor cells into or creating a partially functional human immune system[1] in a live mouse, many experimental studies require a severely attenuated host immune response. Three mouse strains we will discuss here, NOD, NSG, and nude, are commonly leveraged in cancer, precision medicine, infectious disease, HIV, immune system, and vaccination research studies for their various immune system defects.
The NOD/ShiLtJ strain of non-obese diabetic (NOD) immunodeficient mice is susceptible to type 1 (autoimmune) diabetes and is commonly used as a polygenic model organism for the disease. This strain exhibits a decreased innate immune response with lower than average numbers of immune cells, including natural killer (NK) cells, macrophages, and antigen presenting cells (APC), and low hemolytic complement activity. NOD is also commonly used as a background for immunodeficient mouse strains and in autoimmunity and tolerance research. When NOD is used as the background strain for severe combined immunodeficiency (scid) mice that are homozygous recessive for the Prkdcscid allele, the scid mice demonstrate low levels of leakiness, or increasing levels of functional B and T cells over time. Interestingly, the severe combined immunodeficiency mutation results in NOD mice that are diabetes resistant. The NOD mouse strain is also the background strain for a higher-order immunodeficient mouse model, the NOD scid gamma (NSG) strain, that will be introduced shortly.
NOD-scid mice are commonly used for patient-derived xenografts (PDXs), where human cancer xenografts (cells or tissue) from a patient’s tumor can be transplanted into PDX mice to characterize cancer growth and determine the effectiveness of various therapies. NOD-scid mice can also be humanized by the introduction of adult human immune cells to study human immune responses. Naturally, PDXs require immunodeficient host strains to prevent rejection of xenografts. Several other mouse strains are also used for patient-derived xenografts, including scid, Rag2-knockout, and athymic nude mice, which will also be discussed.
NSG is a brand name used for a strain of severely immunocompromised mice that are homozygous for both the Prkdcscid allele and a null allele for the IL2 receptor common gamma chain (IL2rgnull) on the NOD background. The homozygous scid mutation prevents the production of functional B and T cells in the mouse, and the homozygous IL2rgnull mutation compromises cytokine production, resulting in NK cell deficiency. These extremely immunodeficient mice can be used for engrafting human cells and tissues, including CD34+ hematopoietic stem cells (HSC), patient-derived xenografts, peripheral blood mononuclear cells (PMNC), and stem cells. This model is commonly used to study the human immune system, cancer, human immune cells, stem cells, diabetes, and human immune function.
Nude, or athymic, mice are another immunocompromised mouse strain that is used for human xenografts, which make them an excellent model for cancer research. This strain of mice was discovered in the 1960s and is almost completely hairless, hence the “nude” moniker. The strain is homozygous for a null Foxn1 mutation (Foxn1nu), which prevents the formation of functional thymus epithelia and normal hair growth. The lack of thymus gland in these mice prevents the production of both antibodies (with the exception of IgM antibodies) and functional T cells. The lack of thymus is convenient for experiments that would otherwise require numerous thymectomy procedures. Nude mice are commonly used in dermatology and endocrine research, as well as studies characterizing T cell deficiencies and thymus disorders.
Immunocompromised mice engrafted with human cells or tissues is one way to study human disease. Another way of studying human disease is to genetically humanize the mouse. With this, genes from the human immune system are placed within the mouse which enables the evaluation of therapies relevant to human health in an in vivo environment. As one example, mice with humanized immune genes have been used in COVID-19 studies in order to evaluate treatments and develop vaccines during the pandemic. When creating these models, human genes are often randomly inserted into the mouse genome.
Another way to humanize the mouse is to use a specific gene-targeted approach. In this way, the mouse genes are replaced to express human versions of those genes. This allows researchers to study human genes that contain gene mutations within a native and controlled genetic environment. Overall, researchers need to evaluate their field of research, what gene they’re studying, and which model type would be appropriate to them when they decide how to make humanized mice.
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Several transgenic humanized models carrying small-scale partially humanized gene expression units for human ACE2 receptors have been generated and studied. However, there are limitations to these partial humanized models and thus there is room for improvement for effectively studying SARS-CoV-2 infection. Of what is currently available, the clinical signs, recovery, and transmission vary between and within these models. Though there are humanized mice in use for COVID-19 research, there is a need for better humanized mice that are generated by replacing the genomic ACE2 mouse locus with the entire human ACE2 locus. As more accurate humanized mouse models are created for the purpose of studying COVID-19, researchers will have the tools they need to develop more effective treatments and vaccines.
When it comes to using humanized mouse models in genetic research, the future is bright. As new technologies continue to be developed, humanized strains are becoming increasingly more complex. By using these sophisticated animal models, scientists have more options for studying their human diseases of interest. Whether they’re used in the research of infectious diseases and human disorders, or the study of how the human body would react to certain treatments, humanized mice will only become more essential for scientists around the world.
[1] Zhang B, Duan Z, Zhao Y. 2009. Mouse models with human immunity and their application in biomedical research. J Cell Mol Med 13(6): 1043-58.
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