Artificial Human Liver May Hasten Drug Development

The technique could lead to more accurate testing of potential medications.

All experimental drugs must first be evaluated in lab animals before they can be administered to humans. Mice are frequently used for such tests. However, liver enzymes in mice differ from those in humans, and so differ in how they break down, or metabolize, drugs. As a result, research drugs that are shown to be safe in mice may unpredictably break down to create harmful metabolites in humans.

To avoid this hurdle, several research teams have been trying to “humanize” mice, sometimes by transplanting human liver cells into the animals. But for these techniques to work, the mouse’s own liver must be disabled, along with its immune system to avoid an attack on the transplanted human cells. With these techniques, it may take weeks or months for the human liver cells to latch onto and expand in the mouse liver.

In the new study, Dr. Alice A. Chen of the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) and her colleagues generated improved artificial human liver tissues that can begin functioning in mice in less than a week without harming their immune systems or liver. The research was supported in part by US National Institutes of Health (Bethesda, MD, USA) NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Biomedical Imaging and Bioengineering (NIBIB), and National Cancer Institute (NCI).

To create the artificial liver, the scientists grew human liver cells (hepatocytes) mixed with supportive mouse cells called fibroblasts. The cells were then encapsulated with human liver endothelial cells in a disc-shaped polymer scaffold. The endothelial cells secrete compounds that help keep hepatocytes alive and functioning, and the polymer gel scaffold protects against immune system attack. The method was described in the July 11, 2011, online early edition of the journal Proceedings of the [US] National Academy of Sciences.

The researchers demonstrated that when the liver tissue is implanted in the mouse body cavity, it becomes integrated into the animal’s circulatory system within one week. As a result, drugs can reach the liver, and human proteins produced by the liver can enter the bloodstream.

To assess the function of the artificial livers, the scientists gave the mice drugs that are known to break down differently in humans. They found they were then able to detect drug byproducts that are typically generated only by human livers.

“The idea that you could take a humanized mouse and identify these metabolites before going to clinical trials is potentially very valuable,” Dr. Chen stated. With additional study, the technique might able to detect problematic drugs before they are evaluated in humans. It might also help in the study of human liver disease and infections.

Related Links:
Massachusetts Institute of Technology
US National Institutes of Health