January 27’s Medical Research Conference featured two experts in the liver,
Steve Choi, MD, assistant professor of medicine (Gastroenterology), and
Anna Mae Diehl, MD, professor of medicine and chief of the
Division of Gastroenterology. Both addressed recent work that’s led to novel approaches for understanding the underlying mechanisms behind liver disease.
Decreasing hepatitis C virus
Choi’s talk, “Hedgehog Signaling- A New Target in Viral Hepatitis,” focused on the role of permissive cell lines, including Huh 7.5, in creating a liver environment that allows for the Hepatitis C virus (HCV) to replicate.
Choi, who works with HCV patients at the VA, hopes his approach leads to novel therapies for HCV. Veterans, especially Vietnam-era vets, are particularly vulnerable to HCV infection. Though the current treatment model of Interferon and Ribavirin works in the majority of patients, less than half of HCV patients with genotype one are successfully treated with this protocol.
He began his talk by listing some barriers to HCV research: The virus is very difficult to grow in the lab, and the only animal model for the disease is a chimpanzee. Furthermore, there’s no definitive proof that hepatocytes, the liver cells thought to be the primary target cell for HCV infection, are conduits of disease. But promising new scholarship has pointed to the hedgehog signaling pathway as being the sites of HCV activation.
The question then, for Choi, was to see if inhibiting the hedgehog signaling pathway could lead to a decrease of HCV RNA. Choi found that it did, and the opposite, upregulating hedgehog signaling in Huh7.5 cells, increased cell permissiveness.
Choi believes that existing drugs that mediate hedgehog signaling can be useful therapeutic agents against HCV.
Fixing broken livers
Anna Mae Diehl’s lecture, “Fixing Broken Livers,” also discussed the hedgehog pathway and the role of morphogens, molecules that dictate tissue development, in liver disease.
“I got into research to be a better doctor,” Diehl explained. “A hepatologist doesn’t often ease suffering and prolong life.”
That may be because one of the liver’s key features, its ability to regenerate cells, is its most confounding. In healthy people, the liver replaces stressed or destroyed cells daily and without much effort. But in patients with cirrhosis, dying liver tissue often triggers more scaring and a subsequent increased risk of liver cancer. Diehl’s work was guided by three central questions: How does liver cell death trigger repair? What leads to disrepair? How does disrepair lead to further disease?
[quote float="right"]I got into research to be a better doctor[/quote] Through a series of knock out mouse models, Diehl and her colleagues began to answer these questions, and in doing so conjured a new, and in Diehl’s word “heretical,” view of how liver cells, and the hedgehog pathway, function. What she found was that dying mature liver cells produce Hedgehog ligands, which stimulate hepatic stellate cells, a type of resident liver stromal cell, to become myofibroblasts and make scar tissue. Much to Diehl’s surprise, when she knocked out the hedgehog pathway in myofibroblasts, she not only got rid of them and reduced liver scarring, but also eliminated progenitor cells which ultimately give rise to replacement hepatocytes and bile duct cells.. These findings indicated that the myofibroblasts either produced growth factors that the liver progenitors needed to survive, or that the myofibroblasts were, themselves, the primitive precursors of the hepatocyte and bile duct cells.
To solve the mystery, Diehl used double transgenic mice to label myofibroblast cells and their progeny. When they stained the cells from the mice, they saw that mature-appearing bile duct and hepatocytes were marked.
“The only way that could happen is if these more mature liver cells were the children (that is, the progeny) of the myofibroblasts,” said Diehl.
Until now, the thinking has been that liver repairs itself because residual surviving mature hepatocytes and bile duct cells proliferate to replace liver cells that were killed, but Diehl’s work suggests that dead liver cells can also be replaced by cells that are derived from myofibroblastic cells that accumulate during liver injury. Her findings demonstrate that the Hedgehog pathway controls the fate of these myofibroblastic progenitor cells. Pathway activation is needed for such cells to form so that the healing process can begin.
However, when pathway activation is sustained and excessive, the progenitor cells become “trapped” in their myofibroblastic state and produce scar, rather than transitioning to form replacement liver cells. In a patient with cirrhosis, the liver is a site of sustained hedgehog pathway activity; myofibroblastic cells and scar progressively accumulate, while residual healthy liver tissue gradually withers away because the dead liver cells cannot be replaced. This discovery suggests that liver disease patients develop cirrhosis when they have too much of a good thing (i.e., excessive Hedgehog pathway activity), and raises the possibility that doctors might eventually be able to predict who will develop cirrhosis by identifying the genetic and environmental factors that disrupt normal regulation of the Hedgehog pathway.
“What we have now is an exciting working model,” said Diehl. Eventually, if researchers could modulate, or redirect, the hedgehog pathway in a selective way, novel therapies to reverse, and perhaps even to prevent, cirrhosis are within reach.
