Science Editor

The adult nervous system is notoriously unable to regenerate itself after an injury - if Zeus' attack eagle had gone for the brain instead of the liver, Prometheus would not have lasted a week. So it's rather ironic that in the March 30 Science, researchers from the University of California, San Diego identify a nerve growth factor, or neurotrophin, receptor as being the key to liver regeneration.

In fact, neurotrophin' is pretty much a misnomer. The p75 neurotrophin receptor is "almost ubiquitously expressed in the body," including in the lung, gut, muscles, pancreas and on certain cells of the immune system, Katerina Akassoglou, assistant professor of pharmacology at the UCSD School of Medicine, told BioWorld Today. "But very little is known about its role outside of the nervous system."

Even in the brain, the naming confusion continues apace. The p75 neurotrophin receptor is known mainly for its role in apoptosis, or cell death. To actually cause nerve growth, neurotrophins bind to other receptors.

Akassoglou, who is the Science paper's senior author, described herself as "very interested in studying tissue repair." That makes the liver a natural place to look; as an unhappy Prometheus could attest, it has a very high capacity for regeneration.

Clinical studies have shown that the p75 neurotrophin receptor is upregulated in hepatic stellate liver cirrhosis. The assumption had been that this upregulation leads to apoptosis, since that is what the receptor does in the brain.

But Akassoglou and her team found something very different. The role of the p75 neurotrophin receptor "was not apoptosis - it was differentation," of new liver cells, Akassoglou explained.

The p75 neurotrophin receptor was expressed on hepatic stellate cells, support cells in the liver that are activated in response to injury and promote the forming of new liver cells.

Double knockouts that lack both plasminogen (which causes them to develop liver disease) and neurotrophin receptor lived less than half as long, on the average, as mice lacking only plasminogen, suggesting the neurotrophin receptor was protecting the single knockouts from the liver disease.

The finding, Akassoglou said, was unexpected: "Hepatic stellate cells are a target for fibrosis, because they secrete a lot of collagen." Collagen is an important part of the tissue response to injury, but too much of it leads to scarring.

Akassoglou said her team plans to study whether the effects of the receptor are a general feature of liver disease or only happen in response to certain types of damage. Long term, she hopes to determine whether manipulating the p75 neurotrophin can be used therapeutically to impact tissue repair.

For now, her team's results suggest that what to do with hepatic stellate cells may depend on the stage of liver disease. Late-stage liver disease, when there are few liver cells left that can proliferate, might benefit from the current approach of depleting hepatic stellate cells. But in early-stage liver disease with less fibrosis and liver cells that are still capable of regenerating, targeting hepatic stellate cells to stimulate liver cells to proliferate might be the more promising approach. "It's when fibrosis is excessive that the problem starts," Akassoglou said.