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News

The liver is the only human organ capable of regenerating itself. However, it loses this unique ability once damage to the organ is severe, as can happen due to ongoing heavy alcohol use. Once a liver has incurred enough damage to lead to chronic liver disease, a liver transplant is the only treatment option. Noting the scarcity of available donor organs and the significant risks associated with transplant surgery, a team of researchers, led by Dr. Holger Willenbring, has been working to establish novel means of liver regeneration.

Willenbring, a professor of surgery at the University of California, San Francisco (UCSF) and his team recently demonstrated in a mouse study that healthy new liver cells could be regenerated within the organ itself. The scientists, working closely with the laboratory of Dr. Dirk Grimm of Heidelberg University Hospital in Germany, used a virus to convert the very cells that drive liver disease into healthy cells, improving liver function and reducing damage at the same time.

“Part of why this works is that the liver is a naturally regenerative organ, so it can deal with new cells very well. What we see is that the converted cells are not only functionally integrated in the liver tissue, but also divide and expand, leading to patches of new liver tissue,” said Willenbring, who is also associate director of the Liver Center at UCSF and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research.

Liver failure occurs when healthy cells called hepatocytes are damaged by alcohol and diseases such as hepatitis C or fatty liver disease. The gaps these cells leave are filled with myofibroblasts, which generate scar-like tissue and act like patches to help keep the liver functioning. However, left untreated, the liver may become so seriously scarred that it can no longer heal itself. Once the liver has more “patches” than functional tissue, it begins to fail. Willenbring’s team figured out how to transform myofibroblasts into healthy hepatocytes using a cocktail of liver gene switches called transcription factors.

Once the researchers discovered how to change myofibroblasts into healthy cells, there was still the problem of getting the transcription factors into a scarred liver in order to convey these instructions to the cells. The solution was for the researchers to pack a cold-related virus called an adeno-associated virus, or AAV, with their transcription factors and use it to infect myofibroblasts in liver-damaged mice. Once inside the myofibroblasts, the virus downloaded the transcription factors, which transformed the infected cells into functional hepatocytes.

Although the number of new cells was relatively small – less than one percent of all hepatocytes in the treated mice – it was sufficient to reduce fibrosis (scarring of the liver) and improve liver function. While further work is needed to evaluate this approach for use in humans, this new research indicates that this approach could result in a more efficient and stable improvement of liver function than cell transplant approaches.

Presently, said Willenbring, “A liver transplant is still the best cure. This is more of a patch. But if it can boost liver function by just a couple percent, that can hopefully keep patients’ liver function over that critical threshold, and that could translate to decades more of life.”