Liver Cells Switch Identities to Grow New Tissue

By studying a rare liver disease called Alagille syndrome, scientists from UC San Francisco and Cincinnati Children’s Hospital Medical Center have discovered the mechanism behind an unusual form of tissue regeneration that may someday reduce the need for expensive and difficult-to-obtain organ transplants.
The team’s findings, published May 2, 2018, in Nature, show that when disease or injury causes a shortage in one critical type of liver cell, the organ can instruct another type of cell to change identities to provide replacements.

This discovery was made in mice, but in years to come may lead to a viable treatment for human disease. If ongoing follow-up studies succeed, the medical world may gain an alternative method for repairing tissue damage that does not require manipulating stem cells to grow organs from scratch in a lab dish.

“We have known for a long time that the liver has more ability to regenerate than other organs. Only recently have we had the tools to study this ability in depth. Now we have a high-level understanding,” said Stacey Huppert, PhD, a developmental biologist in the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children’s, and one of the new paper’s senior authors.

“Our study shows that the form and function of hepatocytes – the cell type that provides most of the liver’s functions – are remarkably flexible. This flexibility provides an opportunity for therapy for a large group of liver diseases,” said UCSF’s Holger Willenbring, MD, PhD, also a senior author of the study and a professor in the Department of Surgery. Willenbring is a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and the Liver Center at UCSF.

What Is Alagille Syndrome?

Alagille syndrome (ALGS) is a rare, inherited genetic disorder caused by deficiencies in a biological pathway called Notch. ALGS is best known for disrupting the liver’s plumbing system, which consists of tubes called bile ducts that deliver bile made in the liver to the intestine. The disorder occurs in about one in 30,000 people, and in most cases, the problems caused by the condition emerge during infancy or early childhood.

The extent of the condition can range from having too few or too narrow bile ducts to missing all bile ducts in the liver. As a result, the bile that normally helps the body digest fat and carry away toxins backs up inside the liver where it causes severe damage. In many patients with ALGS, bile duct function can be managed and sustained. However, up to 50 percent of patients eventually need a liver transplant, often during childhood.

A Quicker Method of Self-Repair

Every day, the liver takes a beating as it processes everything from medications to alcohol. All these “insults” have prompted the liver to develop a rapid healing ability that does not rely on stem cells, the authors said.

“In addition to making more copies of themselves, liver cells can switch their identity to produce a liver cell type that is lost or, in the case of severe ALGS, never formed,” Willenbring said.

“Previous research has detected adaptive reprogramming in other organs, but it typically involves only a few cells at a time. Our study shows that cells switch their identity at a massive rate in the liver,” Huppert added.

Discovering this phenomenon and learning how it works took nearly five years. The team included co-first authors Johanna Schaub, PhD, and Simone Kurial from UCSF and Kari Huppert from Cincinnati Children’s.

The researchers generated mice that lack cholangiocytes, the type of liver cell that forms bile ducts. Like patients with severe ALGS, these mice quickly developed signs of liver injury. However, over time the mice’s symptoms improved because hepatocytes converted into cholangiocytes and formed fully functional bile ducts.

In July 2017, another study published in Nature reported that cholangiocytes can become hepatocytes if their ability to regenerate is impaired. Viewed together, the two studies suggest that switching of cell identity is the main backup mechanism for liver repair.

The new study further shows that the Notch pathway, which is essential for forming bile ducts but defective in patients with ALGS, can be replaced by another pathway. This process is regulated in the injured liver by a substance called transforming growth factor beta. This discovery is a vital step in identifying targets for therapies that might control this process.

Next Steps

Now the research team is working to determine the precise set of proteins, called transcription factors, that work together to carry out the identity-switching process.

“Using transcription factors to make bile ducts from hepatocytes has potential as a safe and effective therapy,” Willenbring said. “With our finding that an entire biliary system can be ‘retrofitted’ in the mouse liver, I am encouraged that this eventually will work in patients.”

In addition to developing a therapy for ALGS, the team hopes to determine whether liver cell switching can benefit those with other types of liver disease.

Funding for this study came in part from the National Institutes of Health (R01 DK107553, P30 DK026743, T32 DK060414, T32 GM008568, R01 DK078640, P30 DK078392), the California Institute for Regenerative Medicine, the A. P. Giannini Foundation, Deutsche Forschungsgemeinschaft, the Jane Coffin Childs Memorial Fund, and the Eli and Edythe Broad Regeneration Medicine and Stem Cell Fellowship.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.