The liver’s amazing ability to repair itself is the stuff of legend and, increasingly, scientific understanding. A new study, for example, has found that liver repair is aided by a diffuse population of rare stem cells. These stem cells produce elevated levels of telomerase, a protein often associated with resistance to aging. In addition, these stem cells express fewer metabolic genes, perhaps to avoid the wear and tear sustained by other liver cell populations.

The new findings, which were uncovered at the Stanford University School of Medicine, appeared April 4 in the journal Nature, in an article entitled, “Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury.” This article demonstrates that in mice, about 3–5% of all liver cells consist of liver stem cells that intensify telomerase production and ease off metabolism. These stem cells, which are evenly distributed through the liver’s lobules, proliferate in place to make clumps of new liver cells, both during regular cell turnover and after liver damage occurs.

The Stanford scientists, led by Steven Aretandi, M.D., Ph.D., used lineage tracing from the telomerase reverse transcriptase (Tert) locus in mice to demonstrate that rare hepatocytes with high telomerase expression (TERTHigh hepatocytes) are distributed throughout the liver lobule.

“During homeostasis, these cells regenerate hepatocytes in all lobular zones, and both self-renew and differentiate to yield expanding hepatocyte clones that eventually dominate the liver,” the authors of the Nature article wrote. “In response to injury, the repopulating activity of TERTHigh hepatocytes is accelerated and their progeny cross zonal boundaries.”

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'—and, some believe, an organism's—life span.

However, stem cells and some cancer cells make enough telomerase to keep their telomeres from shortening, effectively stopping the aging clock and allowing a seemingly unlimited number of cell divisions. 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.

Dr. Artandi’s team, which includes lead author Shengda Lin, Ph.D., wondered whether telomerase expression could serve as a marker to identify the subset of cells responsible for regenerating the liver during normal turnover. These cells, the team surmised, could also serve as the cell of origin for liver cancer.

“These rare cells can be activated to divide and form clones throughout the liver,” said Dr. Artandi. “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.”

“RNA sequencing shows that metabolic genes are downregulated in TERTHigh hepatocytes, indicating that metabolic activity and repopulating activity may be segregated within the hepatocyte lineage,” the Nature article noted. The fact that these stem cells express fewer metabolic genes might be one way to protect the cells from the daily grind faced by their peers, and to limit the production of metabolic byproducts that can damage DNA.

“This may be one way to shelter these important cells and allow them to pass on a more pristine genome to their daughter cells,” Dr. Artandi suggested. “They are not doing all the 'worker bee' functions of normal hepatocytes.”

When Dr. Lin engineered the telomerase-expressing hepatocytes to die in response to a chemical signal and gave the mice with a liver-damaging chemical, he found that those animals in which the telomerase cells had been killed exhibited much more severe liver scarring than those in which the cells were functional.

“You could imagine developing drugs that protect these telomerase-expressing cells, or ways to use cell therapy approaches to renew livers,” commented Dr. Artandi. “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.”

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