July 12, 2011

Recreating human livers, in mice for better drug testing and screening

By growing human liver tissue inside mice, Alice Chen has created “humanized” mouse livers that respond to drugs the same way a human liver does.

“What’s exciting to researchers is this idea that if we can create these mice with human livers, we can basically create a slew of human-like patients to do drug-development screens, or to … develop new therapies,” says Chen, who works in the lab of Sangeeta Bhatia, the John and Dorothy Wilson Professor of HST and Electrical Engineering and Computer Science.

PNAS - Humanized mice with ectopic artificial liver tissues

One obstacle to creating mice with human livers is that liver cells tend to lose their function rapidly after being removed from the body. Another challenge is that until now, creating mice with humanized livers required starting with mice with severely compromised immune systems — which limits their use for studying the immune response to infectious agents such as the hepatitis C virus, or drugs to combat those agents. Furthermore, those approaches rely on liver injury to create an environment in which implanted human liver cells can proliferate.

The process of breeding such mice is very time-consuming: It can take months to produce a single mouse with the right characteristics, Chen says.

To overcome those issues, Chen and Bhatia developed a tissue scaffold that includes nutrients and supportive cells, which preserve liver cells after they are taken from the body. The tissue scaffold is the size, shape and texture of a contact lens, and can be implanted directly into the mouse abdominal cavity.

Using this approach, the researchers can rapidly implant scaffolds in up to 50 mice in a day; it takes about a week for the implanted liver tissue to integrate itself into the mice. The gel that forms the scaffold also acts as a partial barrier to the mouse’s immune system, preventing it from rejecting the implant.

In the PNAS paper, the researchers demonstrated that the implanted liver tissue integrates into the mouse’s circulation system, so drugs can reach it, and proteins produced by the liver can enter the bloodstream. (The mice also retain their own livers, but the researchers have developed a method to distinguish the responses of mouse and human liver tissue.) Unlike existing approaches, this technique can be used on mice with no liver injury and intact immune systems.

To test the function of the humanized livers, the team administered the drugs coumarin and debrisoquine and found that the mice broke them down into byproducts normally generated only by human livers.

Chen and her colleagues are now studying how the humanized livers respond to other drugs whose breakdown products, or metabolites, are already known. That will pave the way to exploring the effects of untested drugs. “The idea that you could take a humanized mouse and identify these metabolites before going to clinical trials is potentially very valuable,” Chen says.

The team is also working toward miniaturizing the implants to the point where hundreds or thousands could be implanted in a single mouse. If successful, that could make the drug development process more efficient and reduce the number of mice needed for drug studies, Chen says.

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