New type of stem cells that regenerates the liver is found

According to a study conducted at the Stanford University School of Medicine, liver stem cells expressing high levels of telomerase restore the organ during normal cellular metabolism or tissue damage. Understanding this process plays an important role in the treatment of diseases such as cirrhosis or liver cancer. The results of the work were published on April 4, 2018 in Nature.

“The liver is a very important source of human disease”, – said professor of medicine Steven Artandi, MD, PhD. “It’s critical to understand the cellular mechanism by which the liver renews itself. We’ve found that these rare, proliferating cells are spread throughout the organ, and that they are necessary to enable the liver to replace damaged cells.”

The function of the liver cells, called hepatocytes, is 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.

Chronic alcoholism or hepatitis infection can cause cycles of damage and renewal that lead to irreversible scarring that impairs the organ’s function. Nevertheless, at present relatively little is known about liver regeneration.

Telomerase is a protein complex that “tops off” the ends of chromosomes after DNA replication.

Most adult cells lack telomerase activity, and the progressive shortening of telomeres serves as a kind of molecular clock that limits the number of cell divisions and, according to some scientists, affects the life span of the body.

However, stem cells and some cancer cells produce enough telomerase to avoid telomere shortening, effectively preventing aging and providing an almost unlimited number of cell divisions.

Mutations that block telomerase activity cause cirrhosis in mice and humans. Conversely, mutations that excessively increase telomerase activity are often found in liver cancers.

Artandi together with Shengda Lin, PhD, decided to find out whether telomerase expression levels can be used as a marker for identifying the population of cells responsible for liver regeneration.

Lin found that in mice, about 3-5% of all liver cells express unexpectedly high levels of telomerase. These cells, characterized by a lower level of expression of genes involved in normal cellular metabolism, are evenly distributed throughout the liver’s lobules. During a natural regular cell renewal 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”, – said 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.”

The fact that these stem cells express fewer metabolic genes might be one of the mechanisms to protect them from the ” deterioration” that cells from their environment encounter. It also limits 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”, – Artandi said. “They are not doing all the ‘worker bee’ functions of normal hepatocytes.”

Lin created 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”, – said Artandi. We are finally beginning to understand how this organ works.”