The Brush: The Human Rat: More Than the Sum of Its Parts

What is the humanization of mice?
Humanized mouse models are mice that scientists modify in the laboratory to host human cells, tissues, genes, or parts of a person’s microbiome. Researchers use humanized mouse models to study aspects of human biology and health in living organisms. Historically, functional studies of human health have relied on ex vivo analyzes and costly clinical trials that are likely to be limited by ethical limitations. Humanized mice are helping researchers study human health in vivo and overcome the limitations of cell culture, tissue culture, and clinical trials.^1,2

How are humanized mice made?
Scientists use several methods to generate humanized mouse models to answer a variety of research questions.³ Many of these techniques rely on immunodeficient mouse strains to ensure long-term immunization of human cells or tissues.⁴ Three common methods of generating humanized mice include: transplanting the human immune system into immunodeficient mice, replacing the mice’s genes with their human counterparts, and transferring germs from the intestine of a human donor into a germ-free mouse.^2,3,5,6

How do researchers use humanized mouse models?
Human immune system mice
The human immune system is fundamentally different from the immune system of mice, so it is difficult to translate research achievements in mice directly into humans. This makes the ability to recapitulate key features of the human immune system in a murine model particularly invaluable. Researchers can use human immune system (HIS) mice that have been vaccinated with functional components of the human immune system to analyze the development and function of the human immune system in vivo. Scientists use HIS mice to study a variety of topics in immunology, including allergies, infectious diseases, and autoimmune diseases, such as systemic lupus erythematosus and ulcerative colitis.³

Humanized mouse tumor models and cancer
Mice that host tumors of human origin facilitate cancer biology and anticancer drug discovery research. Examples of mouse tumor models include cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Researchers inoculate CDX models with human cancer cell lines or inoculate PDX models with primary human cancer samples. PDX mice can reflect patient-specific features of some types of cancer. Scientists use PDX models in cancer research and the development of anticancer drugs for many types of cancer, including lung, colon, pancreatic, head and neck, breast, prostate, and renal cell carcinomas, as well as glioblastoma and melanoma.⁷

Humanized mouse models of the nervous system
Researchers can use humanized mouse models to conduct cost-effective, high-throughput studies of the nervous system and to evaluate preclinical treatments. They culture mice with stem cells or progenitor cells from humans to reflect aspects of human neurobiology and neurodegenerative diseases in vivo.^3,4 The three main types of cells in the central nervous system, neurons, astrocytes, and oligodendrocytes, arise from stem cells and progenitor cells. Scientists have refined protocols for differentiation of stem and progenitor cells into specific types of cells of the nervous system, which has greatly contributed to the understanding of human brain development and neurodegenerative disease.^3,9 For example, scientists are transplanting human glial progenitor cells (hGPCs) into the central nervous system of immunocompromised mice to study nervous system development, and human induced pluripotent stem cells (iPSCs) to study neurodegenerative disorders such as Alzheimer’s disease.^3,4

Humanized mouse models of genetic disorders
Researchers are using humanized mice to develop precision medicine for genetic disorders, which must be tested preclinically in relevant cellular and animal models. It is important that these models contain the human genetic target because therapies for mutations will not work in models that lack the disease-causing human DNA sequence. When scientists implant human cells and tissues into mice, the human components preserve the genetic background of the donor. If the donor is a patient with a genetic disease and the humanized mouse model recapitulates some of the clinical manifestations of the disorder, researchers can test personalized treatments with humanized mice in vivo prior to clinical trials in humans.¹⁰

Mouse models associated with human microbiota
The gut microbiome affects many immune and metabolic diseases, including type 2 diabetes, asthma, inflammatory bowel disease, and cancer. While scientists have identified a causal role for the gut microbiome in some diseases using animal models, it is difficult to untangle the disease-related and lifestyle changes of the microbiota in humans. Researchers are using mice associated with human microbiomes to test how altered gut microbes contribute to disease. HMA mice are germ-free strains in which the human gut microbiota is established through fecal culture. Researchers can examine the pathological phenotypes of germ-free mice colonized with the fecal microbes of patients versus mice colonized with the microbes of healthy individuals.²

references

1. MA Brehm et al., “Humanized mouse models for the study of human disease,” Obesity Diabetic Opin Endocrinol Diabetic17: 120-25, 2010.
2. Arrieta et al., “Mice Associated with Human Microbiomes: A Model with Challenges,” host cell microbe19: 575-78, 2016.
3. Fujiwara, “Humanized mice: a brief overview of their diverse applications in biomedical research,” J Cell Physiol233: 2889-901, 2018.
4. PK Dash et al., “Humanized mice for infectious and neurodegenerative disorders,” Retrovirology18: 1-17, 2021.
5. RW Körner et al., “About mice and men: MHV and mouse coronavirus models as translational approaches to understanding SARS-CoV-2,” Viruses12:1-26, 2020.
6. E. Axton, D. Tanamachi, “Important considerations for the generation of humanized mouse models,” JAX Blog, August 25, 2021, p. 1-6.
7. Tian et al., “Humanized rodent models for cancer research,” Front Uncol10: 1-11, 2020.
8. S. Fu et al. A humanized preclinical mouse model with ectopic ovarian tissue. Exp Thier Med8: 742-46, 2014.
9. X. Zhao, D. Moore, “Neural Stem Cells: Growth Mechanisms and Disease Modeling,” precision cellular tissue, 371: 1-6, 2018.
10. a. Artsma Ross, M. Van Putten, “Using genetically humanized animal models in personalized medicine approaches,” Dis mechanical model13: 1-6, 2019.