Newly Discovered Liver Cells Regenerate Liver Without Forming Tumors

The means by which the liver repairs itself is still a matter of debate. Now a new study from the University of San Diego has discovered a population of liver cells that do a better job at regenerating liver tissue than ordinary liver cells, or hepatocytes. This study has identified a cell population called “hybrid hepatocytes” that are able to regenerate liver tissue without giving rise to cancer.

This latest study was led by Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at University of San Diego. Karin and his colleagues published their study in the August 13th edition of the journal Cell, and their paper is the first to identify these so-called “hybrid hepatocytes.” Karin and his coworkers also showed that hybrid hepatocytes are able to regenerate liver tissue without giving rise to cancer. Although the majority of the work described in this study was done in mouse models, Karin and his group also found similar cells in human livers.

Of all major organs, the liver has the highest capacity to regenerate. This is the main reason some liver diseases, including cirrhosis and hepatitis, can often be cured by transplanting a piece of liver from a healthy donor. The liver’s regenerative properties were previously credited to a population of adult stem cells known as oval cells. However, recent studies concluded that oval cells do not give rise to hepatocytes, since oval cells tend to make bile duct cells. These discoveries prompted researchers to begin looking for other cell populations in the liver that serve as the primary source of new hepatocytes in liver regeneration.

To find this new cell population, Karin and others traced the cells responsible for replenishing hepatocytes following chronic liver injury after laboratory animals were fed the liver toxin carbon tetrachloride. The liver regeneration that was stimulated by carbon tetrachloride-induced liver damage was traced to a unique population of hepatocytes in one specific area of the liver, called the “portal triad.” The portal triad is a region of the liver named after its triangular shape and its three major components: the hepatic artery, the hepatic portal vein, and the hepatic ducts, or bile ducts. The portal triad is also known by its clinical term, portal hepatis, transverse fissure and portal fissure. The portal triad serves as a blood-vessel gateway or entrance of the liver’s hepatic lobule. These special liver cells that reside in the portal triad hepatocytes undergo extensive proliferation and replenish liver mass after chronic liver injuries. Since these cells are similar to normal hepatocytes, but express low levels of bile duct cell-specific genes, Karin and his team dubbed these cells “hybrid hepatocytes.”

Portal Triad

Many other research labs around the world are attempting to use induced pluripotent stem cells (iPSCs) to repopulate diseased livers and prevent liver failure. “Although hybrid hepatocytes are not stem cells, thus far they seem to be the most effective in rescuing a diseased liver from complete failure,” said Joan Font-Burgada, PhD, postdoctoral researcher in Karin’s lab and first author of the study.

While iPSCs hold a lot of promise for regenerative medicine, it might be theoretically difficult to ensure that they stop proliferating once their therapeutic job is done. As a result, iPSC-derived cells might pose a significant risk for tumor formation.  To test the safety of hybrid hepatocytes, Karin’s team examined three different mouse models of liver cancer. They found no signs of hybrid hepatocytes in any of the tumors, leading the researchers to conclude that these cells do not contribute to liver cancer caused by obesity-induced hepatitis or chemical carcinogens.

“Hybrid hepatocytes represent not only the most effective way to repair a diseased liver, but also the safest way to prevent fatal liver failure by cell transplantation,” Karin said.

New Liver Stem Cell Might Aid in Liver Regeneration

For patients with end-stage liver disease, a liver transplant is the only viable option to stave off death. Liver failure is the 12th leading cause of death in the United States, and finding a way to regenerate failing livers is one of the Holy Grails of liver research. New research suggests that one it will be feasible to use a patient’s own cells to regenerate their liver.

Researchers at the Icahn School of Medicine at Mount Sinai have discovered that a particular human embryonic stem cell line can be differentiated into a previously unknown liver progenitor cell that can differentiate into mature liver cells.

“The discovery of the novel progenitor represents a fundamental advance in this field and potentially to the liver regeneration field using cell therapy,” said Valerie Gouon-Evans, the senior author of this study and assistant professor of medicine at the Icahn School of Medicine. “Until now, liver transplantation has been the most successful treatment for people with liver failure, but we have a drastic shortage of organs. This discovery may help circumvent that problem.”

Gouon-Evans collaborated with the laboratory of Matthew J. Evans and showed that the liver cells that were made from the differentiating liver progenitor cells could be infected with hepatitis C virus. Since this is a property that is exclusive to liver cells, this result shows that these are bona fide liver cells that are formed from the progenitor cells.

One critical step in this study was the identification of a new cell surface protein called KDR, which is the vascular endothelial growth factor 2. KDR was thought to be restricted to blood vessels, blood vessels progenitor cells (EPCs), and blood cells.  However, the Evans / Gouon-Evans study showed that activation of KDR in liver progenitor cells caused them to differentiate into mature liver cells (hepatocytes).  KDR is one of the two receptors for VEGF or vascular endothelial growth factor.  Mutations of this gene are implicated in infantile capillary hemangiomas.

KDR Protein Crystal Structure
KDR Protein Crystal Structure

The next step in this work is to determine if liver cells formed from these embryonic stem cells could potentially facilitate the repair of injured livers in animal models of liver disease.