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Liver Regeneration May Be Simpler Than Previously Thought

The findings of the study showed that a regenerating liver does not behave as a developing embryo. Instead, regeneration could actually be only due to an increase in cells that multiply through regular cell divisions, a process called hyperplasia.
by Staff Writers
Bethesda MD (SPX) Apr 17, 2007
The way the liver renews itself may be simpler than what scientists had been assuming. A new study, appearing in the April 13 issue of The Journal of Biological Chemistry, provides new information on the inner workings of cells from regenerating livers that could significantly affect the way physicians make livers regrow in patients with liver diseases such as cirrhosis, hepatitis, or cancer.

"The human liver is one of the few organs in the body that can regenerate from as little as 25 percent of its tissue," says Seth Karp, assistant professor of surgery at Harvard Medical School, Boston, and main author of the study. "It is not known how the liver does it, but our results provide some details of what makes the liver so unique."

Although organ regeneration has been observed in many animals, the details of how it happens at the cellular level are still not completely understood. So far, scientists have shown that cells that participate in tissue regeneration behave as if they were part of a growing organ in an embryo. In other words, the cells act as if the liver is growing, as do other organs in a developing embryo.

Many of the proteins that induce organ regeneration have been identified and scientists are now trying to make organs regrow by stimulating these proteins. Regrowing livers this way would be especially useful for patients whose livers are so damaged - say, by a tumor that has spread to most of the liver - that a large part would be removed. Unless such patients receive the right amount of liver transplant from an organ donor, they do not always survive. Quickly stimulating the growth of the remaining portion of their liver could be their only chance of survival.

To investigate how the liver regenerates, Karp and his colleagues set out to determine which proteins are involved in the regenerating cells. The scientists were also interested in testing whether regenerating cells behave like embryonic ones, as is commonly assumed for other organs. New processes may explain why the liver is so uniquely capable of renewal and repair after injury, the scientists thought.

Karp's team considered two samples of mice. The first consisted of embryonic mice at various stages of development while the second was composed of adult mice to which two-thirds of their liver were removed. Using techniques such as DNA microarrays - which determine which genes are active in a cells - and software programs that analyze the collected information, the scientists listed all the proteins that help the cells grow and proliferate in both samples.

The results were unexpected. The researchers noticed that only a few proteins were common to both processes. Proteins called transcription factors, which affect DNA in the cell's nucleus, were highly involved in the development of embryos' livers but not in adult liver regeneration. Instead, proteins that help cells proliferate were active in both the developing and regenerating livers.

These findings showed that a regenerating liver does not behave as a developing embryo. Instead, regeneration could actually be only due to an increase in cells that multiply through regular cell divisions, a process called hyperplasia.

The new results may also have important medical implications. Transcription factors are known to be more difficult to manipulate than the other identified proteins. Since the transcription factors were not present in regenerating livers, it might be easier to stimulate liver regeneration by only activating the other identified proteins.

"These results are very encouraging," Karp says. "Not only did we discover that the number of proteins involved in liver regeneration is relatively low, but they don't include transcription factors, so we may be closer to being able to stimulate liver regeneration than we thought."

The next step will be for scientists to understand whether the regenerating cells are stem cells. Studies have shown that adult stem cells are involved in the repair of many organs, but in the case of the liver, the cells repairing it through regeneration may simply be regular cells, not stem cells.

"We think that the liver regrows through a relatively simple process, which could explain its prodigious ability to repair itself," Karp says.

U.S culture hurting EU livers?
by Ed Susman UPI Medical Correspondent
Barcelona (UPI) Spain, April 11 - Fatty liver, a condition that can lead to cirrhosis, liver failure and the need for organ transplantation, appears to be another part of the import of American fast-food culture to Europe, doctors said Wednesday.

"We estimate that in Spain about 2 to 3 million people among the 40 million inhabitants of the country have fat in their liver," said Jesus Prieto, professor of general pathology at the University of Navarra in Pamplona, "and that 25 percent of those patients have developed non-alcoholic steatohepatitis (NASH)."

Non-alcoholic steatohepatitis, often called "silent" liver disease, resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. The major feature in NASH is fat in the liver, along with inflammation and damage.

"We are seeing an increase in this disease across Europe," Rafael Esteban, professor of medicine at Hospital Valle Hebron in Barcelona, told United Press International as the 42nd annual meeting of the European Association for the Study of the Liver got under way in Barcelona. "It appears to follow the 'fast food' dining that is now moving rapidly across Europe."

Exactly how many people have the disease is difficult to measure, Prieto said. People with NASH may feel well and are not aware they have a liver problem. However, he added that NASH occurs more frequently in individuals who are overweight or obese and have diabetes.

Esteban suggested that people who have diabetes or are overweight should have doctors carefully monitor liver function tests. Abnormalities in these tests are likely to pick up hints of disease and give doctors the opportunity to diagnose the disorder, he said.

"There is a lot more NASH in the United States," Prieto told UPI at the press briefing, conducted as more than 5,600 clinicians and allied health care professionals gathered for the scientific sessions that continue through Sunday.

Prieto said that NASH is not a benign disorder. "The disease can progress to cirrhosis of the liver and can result in the need for liver transplantation. About 5 percent of the people that undergo liver transplantation in Spain are being treated for complications of NASH," he said.

Cirrhosis causes permanent damage and scarring to the liver, and that can cause the organ to malfunction. In the United States, about 2 to 5 percent of patients have NASH, and another 10 to 20 percent of people are at risk of the disease because of abnormal levels of fat in the liver, although not all of the people will develop an associated disorder, non-alcoholic fatty liver disease.

Esteban said the concern over liver disease has been heightened by recent surveys and reports that children in Europe have a greater rate of obesity, which also tends to parallel "fast food" diets as American-style eateries proliferate.

"These studies in children show us that this epidemic in NASH will continue to expand over time," he said.

In the United States, the rate of obesity in adults has doubled, while the rate in children has tripled in the past decade, probably leading to the increase of both NASH and fatty liver disease. Obesity also contributes to diabetes and high blood cholesterol, which can further complicate the health of someone with NASH.

Source: United Press International

Article: "Restoration of Liver Mass after Injury Requires Proliferative and Not Embryonic Transcriptional Patterns" by Hasan H. Otu, Kamila Naxerova, Karen Ho, Handan Can, Nicole Nesbitt, Towia A. Libermann, and Seth J. Karp

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Rhesus Macaque Genome Helps Illuminate What Makes Us Human
Washington DC (SPX) Apr 16, 2007
Researchers have sequenced the genome of the relatively ancient rhesus macaque (Macaca mulatta), providing perspective into how humans are genetically different from our primate relatives. In addition to benefiting human health research in areas as diverse as HIV and aging, the genome enhances understanding of primate evolution. The macaque genome research appears in the 13 April issue of Science published by AAAS, the nonprofit science society.

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