In adult mammals, the liver is the most regenerative organ, capable of significant regrowth following injury. Why is this the case? Researchers here point to a small subset of liver cells in mice that are distinguished by telomerase expression, and while mice and humans have quite different telomerase and telomere dynamics, indirect evidence suggests that a similar population may exist in our species. Significant telomerase expression is the characteristic of stem cells that allows for unlimited replication: telomerase acts lengthen telomeres, the caps at the ends of chromosomes that shorten with each cell division. When too short, cells enter senescence or destroy themselves. Lacking telomerase, the vast majority of cells can only divide a set number of times.
This segregation between a few privileged stem cells and the vast mass of restricted somatic cells is the primary strategy by which multicellular life keeps the incidence of cancer to a manageable level. Mutations occur constantly, and evolution requires mutation, even when harmful to individuals, but it is much harder for mutational damage to cause somatic cells to run amok, given their inherent limitations. Unsurprisingly then, researchers are interested in the source of the liver's regenerative capacity not just to improve on it, or to find ways to regenerate other organs, but also to gain insight into the origins and peculiarities of liver cancer.
A subset of liver cells with high levels of telomerase renews the organ during normal cell turnover and after injury, according to researchers. The cells are distributed throughout the liver's lobes, enabling it to quickly repair itself regardless of the location of the damage. Understanding the liver's remarkable capacity for repair and regeneration is a key step in understanding what happens when the organ ceases to function properly, such as in cases of cirrhosis or liver cancer. "It's critical to understand the cellular mechanism by which the liver renews itself. We've found that rare, proliferating cells are spread throughout the organ, and that they are necessary to enable the liver to replace damaged cells. We believe that it is also likely that these cells could give rise to liver cancers when their regulation goes awry."
The liver's cells, called hepatocytes, work to filter and remove toxins from the blood. The liver is unique among organs in its ability to fully regenerate from as little as 25 percent of its original mass. Stem cells and some cancer cells make enough telomerase to keep their telomeres from shortening. Mutations that block telomerase activity cause cirrhosis in mice and humans. Conversely, mutations that kick telomerase into high gear are frequently found in liver cancers. Telomerase is a protein complex that "tops off" the ends of chromosomes after DNA replication. Without its activity, protective chromosomal caps called telomeres would gradually shorten with each cell division. Most adult cells have little to no telomerase activity, and the progressive shortening of their telomeres serves as a kind of molecular clock that limits the cells' life span.
Researchers found that, in mice, about 3-5 percent of all liver cells express unusually high levels of telomerase. The cells, which also expressed lower levels of genes involved in normal cellular metabolism, were evenly distributed throughout the liver. During regular cell turnover or after the liver was damaged, these cells proliferate in place to make clumps of new liver cells. "These rare cells can be activated to divide and form clones throughout the liver. As mature hepatocytes die off, these clones replace the liver mass. But they are working in place; they are not being recruited away to other places in the liver. This may explain how the liver can quickly repair damage regardless of where it occurs in the organ. You could imagine developing drugs that protect these telomerase-expressing cells, or ways to use cell therapy approaches to renew livers. On the cancer side, I think that these cells are very strong candidates for cell of origin. We are finally beginning to understand how this organ works."