Liver Regeneration through Telomerase Repopulation
Myriad genetic and epigenetic alterations are required to drive normal cells toward malignant transformation. These somatic events commandeer many signaling pathways that cooperate to endow aspiring cancer cells with a full range of biological capabilities needed to grow, disseminate and ultimately kill its host.
Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and are particularly vulnerable due to progressive shortening during each round of DNA replication and, thus, a lifetime of tissue renewal places the organism at risk for increasing chromosomal instability.
Telomere dysfunction can produce the opposing pathophysiological states of degenerative aging or cancer with the specific outcome dictated by the integrity of DNA damage checkpoint responses.
Hepatocytes are replenished gradually during homeostasis and robustly after liver injury. In adults, new hepatocytes originate from the existing hepatocyte pool, but the cellular source of renewing hepatocytes remains unclear.
Now, Stanford scientists have identified a subset of hepatocytes that expresses high levels of telomerase and show that this hepatocyte subset repopulates the liver during homeostasis and injury.
“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. We believe that it is also likely that these cells could give rise to liver cancers when their regulation goes awry.”
“These rare cells can be activated to divide and form clones throughout the liver,” said Artandi, who holds the Jerome and Daisy Low Gilbert Professorship in Biochemistry. “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.”
In the course of their investigation, the team found that, in mice, about 3-5 percent of all liver cells express unusually high levels of telomerase. During regular cell turnover or after the liver was damaged, these cells proliferate in place to make clumps of new liver cells. 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,” Artandi said. “They are not doing all the ‘worker bee’ functions of normal hepatocytes.”
When 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,” said 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.”
