Fausto investigating how liver regenerates and controls its growth

Nelson Fausto

In operating rooms across the country, 4,000 people's lives are saved yearly with liver transplants, yet 10,000 more people are on waiting lists. One hope for changing this equation lies in the hands of the researchers who seek to understand exactly how the liver does what no other organ can do: regenerate.

“ The liver is an enormously exciting area of research in terms of clinical application and basic biology,” says Dr. Nelson Fausto, chair of the School of Medicine's Department of Pathology and an international expert on carcinogenesis and liver regeneration.

After a 70 percent hepatectomy, a surgical excision of 70 percent of the liver, the organ can regrow to its normal size within a matter of weeks. This special ability makes it possible, for instance, for a live person to donate part, or half, of his or her liver. Both the liver in the recipient and the donor will regrow to the sizes required for normal function.

“ The questions we want to answer are the cellular mechanisms of this regeneration. It is basic science research with direct clinical impact,” Fausto said.

Within 24 hours of a hepatectomy, 95 percent of liver cells will have reproduced once. In 48 to 52 hours, about half the cells have reproduced at least twice. The cells return to quiescence once the liver mass is restored.

“ How this is controlled is the question. This amount of growth at any one time is more than you would see in any malignant tumor or anywhere else. Even with this massive proliferation, it never normally gets out of control,” Fausto said.

When it does run out of control, when researchers continually stimulate liver cells with peptides called growth factors, for instance, proliferation can lead to tumors. In a majority of liver tumors in humans, a growth factor called TGF-alpha (transforming growth factor-alpha) is over-expressed.

Fausto said it was originally thought that simply injecting growth factors into liver tissue in culture would result in proliferation of the cells. But that's not the case.

“ We hypothesized that hepatic cells need a priming step in order to proliferate.” In other words, growth factors are essential for cell proliferation and regeneration, but they don't induce it.

To find out what does induce this cell proliferation, Fausto and his colleagues are working with a peptide called tumor necrosis factor (TNF), which increases dramatically in the liver within minutes after a partial hepatectomy. Mice that lack the gene for a specific receptor for TNF either die or have deficient regeneration after a partial hepatectomy or injury caused by chemicals and toxins.

Fausto and his colleagues have traced the “ downstream” effects of TNF in activating genetic templates for liver regeneration, such as proto-oncogenes, transcription factors and the cytokine interleukin-6. They are now working on elucidating how TNF transmits signals to these genes to trigger liver regeneration.

Fausto, a native of Sao Paulo, Brazil, has been chair of the Department of Pathology since he came to the UW in 1994 from Brown University. At Brown, he received a dozen Distinguished Teaching Awards and founded the Department of Pathology. He is the editor-in-chief of The American Journal of Pathology and associate editor of Cancer Research. ¶
Will Morton