Mouse Models to Study Stem Cells

The Mouse as a Disease Model

For several decades, scientists have engaged in research involving various animals to establish mechanisms associated with specific biological activities. These model organisms serve as exemplary representations of human conditions, especially when a specific biological phenomenon shows similarities between the model organism and humans. For example, several genes have been evolutionarily conserved in the animal kingdom and, thus, even the invertebrate fruit fly can be exploited in the identification of gene mutations and candidate genes that result in a specific disease. Among the various animal species that have served as disease models in scientific investigations, the mouse stands as the ideal organism for exploring processes related to the development of human diseases. Mice possess [Page 786]similar physiological features to humans and the ease of their manipulation has generated hundreds of strains that represent different hybridizations or gene mutations. Mice also have been used in determining the effects of radiation, toxins, and chemicals on specific systems of the human body. The first genetic maps were generated based on cloning efforts of disease-associated genes in the mouse. Transgenic approaches also were initially tested in these murine animal models.

The Mouse as a Resource for Embryonic Stem Cells

Pluripotency pertains to the generation of daughter cells that have the potential to differentiate into any cell type. The mouse has been used as the initial animal model in studying embryonic stem cells, which are isolated from the inner cell mass of a developing embryo. Two major features of these cells were first discovered while culturing these cells in the laboratory. First, scientists observed that embryonic stem cells could be cultured indeterminately through a process known as self-renewal, creating more cells from the symmetrical division of each stem cell. When an embryonic stem cell undergoes differentiation, it loses its ability to undergo continuous cell division, which, in turn, results in a cellular phase known as aging. Second, embryonic stem cells are capable of maintaining their status of pluripotency and, thus, in the presence of specific environmental stimuli, can enter the differentiation process and mature into any cell type, similar to the range of cell fates inherently possessed by cells of the inner cell mass.

Previous studies have shown that murine embryonic stem cells engage in highly efficient homologous recombination, which is a feature that distinguishes them from other cell types. The majority of reports describing gene targeting via homologous recombination have been based on manipulations of mouse embryonic stem cells. Because these pluripotent cells are capable of differentiating into any cell type, scientists have conducted experiments that involve injecting these cells into a blastocyst and monitoring the resulting characteristics of the developing embryo. Other in-depth experiments involved the use of embryonic stem cells that harbored genomes with specific mutations of interest. Reporter genes have been integrated into the genome of embryonic stem cells to investigate patterns of gene expression in a wide range of cell types. Manipulated murine embryonic stem cells have been combined with purification methods, resulting in the identification of specific proteins that can possibly be used as novel pharmaceutical reagents. Although a wide range of cellular and genetic manipulations can be performed using murine embryonic stem cells, there are still certain mouse models that do not respond to these in vitro modifications.

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