Building a better mouse (model) for studying human disease

In recent decades, a few genetic strains of mice have proven invaluable to medical researchers in serving as “surrogates” capable of supporting the growth of human cells. These “xenografted mouse models” can give scientists a relevant window into human biology that may point to new therapies and understanding of disease — or at the very least, validate or disprove results from a laboratory dish.

But this process is made especially cumbersome by the need to irradiate animals first to suppress immune systems that would otherwise attack foreign cells. A Morgridge Institute regenerative biology research team has found a novel way to grow human blood stem cells in mice without the damaging step of radiation, opening new possibilities for studying cancer, viruses and immune systems.

“This model will allow scientists to transplant different cell types, with differing growth kinetics, in vivo, escaping the need to insult the organism or engrafted tissue with irradiation or chemicals,” says Brian McIntosh, an assistant scientist – automation in regenerative biology. McIntosh is co-lead author with Regenerative Biology Director James Thomson on a paper appearing online today in Stem Cell Reports.

The newly derived mouse model is a cross of a number of known mutations with a Kit mutation, yielding mice with very poor KIT receptors on the surface of cells. Because of this, it is easier for the donor cells to out-compete the host cells and thrive within the mouse.

McIntosh says these mouse models are especially important in determining whether a promising finding in vitro still has relevance in a living organism, and the only way to currently determine that is in an animal model. “As a scientist, we may have created something in a dish that looks like it has all the right elements and markers to be useful for a particular problem,” he says. “But we still rely on grafting into animal models to validate function.”

The mouse models have already been incorporated into several University of Wisconsin-Madison and commercial studies. For example, UW-Madison pathology Professor Igor Sluvkin is using the mice in a model to study cancer, and cancer biology/infectious disease Professor Shannon Kenney is using them to study certain herpes viruses, such as Epstein Barr Virus, that can be lethal for people undergoing transplantation and have suppressed immune systems.

The Morgridge group also has provided the mice to the Jackson Laboratory, a leading mouse genetics research lab in Bar Harbor, Maine, to improve access throughout the scientific community. Cellular Dynamics International, a Madison company founded on Thomson’s scientific advances, also is using the models to enhance the quality of their cellular products.

Co-authors on the Stem Cell Reports study include Igor Sluvkin (Department of Pathology and Laboratory Medicine), Matthew Brown (UW-Madison Department of Surgery), and Morgridge scientists Bret Duffin, John Maufort and David Vereide.

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