March 29, 2007 (Scientific American)
Gene Activates Liver Repair
Hunting for a way to let the liver heal itself without causing more harm than good
By JR Minkel
Researchers may have identified a master switch that activates the liver's ability to heal itself, suggesting a route to better treatments for liver diseases such as hepatitis and cirrhosis. Mice that lacked the gene showed a marked deterioration in their livers and lived shorter lives than normal mice.
Damage to the liver activates a group of specialized wound-healers called hepatic stellate cells (HSCs), which churn out scaffoldlike collagen fibers that support the growth of new liver cells. "You want the cells to get activated but you don't want them to stay activated for too long," says neurobiologist Katerina Akassoglou of the University of California, San Diego, because the fibers begin substituting for healthy liver tissue, leading to liver failure in people with chronic cirrhosis, for example. But researchers do not know which genes control the process.
Akassoglou and her colleagues thought they had a good candidate in the gene for the p75 neurotrophin receptor (p75NTR), a regulator of cell death in the brain that also switches on soon after liver injuries. Using mice that had a propensity for liver disease, her team created a strain of rodents that lacked the p75NTR gene. The livers of the engineered mice were covered in lesions after 10 weeks, and only half of the animals lived longer than that, compared with more than six months for the unmodified rodents.
The p75NTR protein sits on the surface of HSCs. The group believes that when activated by a still-unknown agent after liver damage, it stimulates a cascade of signals inside the cells that trigger them to begin the healing process, according to results presented in this week's Science. The next step, Akassoglou says, is to determine the role p75NTR plays in later stages of liver disease, to see if shutting it down will stop the harmful production of collagen.
"If you know what the switch is," she says, "and if you know how these cells become quiescent again … then you can start interfering with this process."