Liver Regeneration May Be Easier Than Once Thought

A new study provides new insights into the inner mechanisms of cells from regenerating livers that could considerably affect the way clinicians can make livers regrow in patients with liver diseases such as cirrhosis, hepatitis, or cancer.

Therefore, the manner in which the liver renews itself may be simpler than what researchers had once believed. "The human liver is one of the few organs in the body that can regenerate from as little as 25% of its tissue,” remarked Dr. Seth Karp, assistant professor of surgery at Harvard Medical School (Boston, MA, USA), and lead investigator 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.”

Even though organ regeneration has been observed in many animals, the particulars of how it happens at the cellular level are still not completely understood. Up to now, scientists have demonstrated that cells that contribute to tissue regeneration behave as if they were part of a growing organ in an embryo. The cells act as if the liver is growing, as do other organs in a developing embryo.

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

To investigate how the liver regenerates, Dr. Karp and his colleagues tried to determine which proteins are involved in the regenerating cells. The scientists were also interested in assessing whether regenerating cells behave like embryonic ones, as is typically assumed for other organs. New processes may clarify why the liver is so exclusively capable of renewal and repair after injury, the scientists believed.

Dr. Karp's team evaluated two samples of mice. The first consisted of embryonic mice at various stages of development whereas 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 gathered data, the investigators listed all the proteins that help the cells grow and proliferate in both samples.

The findings were surprising. 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 very 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 results demonstrated that a regenerating liver does not behave as a developing embryo. Instead, regeneration could in reality be only due to an increase in cells that multiply through regular cell divisions, a process called hyperplasia.

The new findings may also have significant medical implications. Transcription factors are known to be more hard 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,” Dr. Karp stated. "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. Research has 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 common cells, not stem cells. "We think that the liver regrows through a relatively simple process, which could explain its prodigious ability to repair itself,” Dr. Karp concluded.

The study was published in the April 13, 2007, issue of the Journal of Biological Chemistry.



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