Good from bad: UCSF scientists turn scar-forming cells into healthy liver cells

Most people know that a healthy liver is key for survival. Unfortunately, maintaining a healthy liver isn’t always easy. There are more than 100 different types of liver disease caused by various factors like viral infection, obesity, and genetics. If left untreated, they can progress to end-stage liver disease, also known as cirrhosis, which effects more than 600,000 Americans and has a high mortality rate. While there is a cure in the form of liver transplantation, there aren’t enough healthy donors available to help out the number of patients who desperately need new livers.

Cirrhosis occurs when liver damage accumulates over time causing the development of scar tissue that eventually replaces healthy liver tissue and impairs liver function. The liver is an amazing organ and can function even with the build-up of scar tissue as long as at least 20% of its composition is healthy cells. This impressive nature is actually a problem because most patients with liver disease aren’t aware of their condition until its progressed past the point of no return.

What’s a damaged liver to do?

So what do patients with end-stage liver disease do if they can’t get a liver transplant? One answer comes in the form of regenerative medicine. Scientists can generate new healthy liver cells in a dish from stem cells derived from the skin cells of patients and could eventually transplant these cells into the damaged liver. However, a major roadblock that prevents this type of cell transplantation therapy from helping patients with liver disease is the built-up scar tissue that prevents the integration of these healthy cells into the damaged liver.

Scientists from UC San Francisco (UCSF) have come up with a new solution to this problem. In a CIRM-funded study published today in journal Cell Stem Cell, UCSF professor Holger Willenbring details a new approach to repairing damaged livers in mice – one that generates good, healthy liver cells from bad, scar-tissue forming cells already present in the damaged liver.

The bad cells in this case are called myofibroblasts. Initially, these cells play an important role in repairing injuries in the liver. They secrete proteins called collagen that form a support structure that helps maintain composition of the liver as it repairs itself. However, if liver damage persists as is the case with chronic injury, the excess buildup of collagen secreted by myofibroblasts causes the accumulation of permanent scar tissue or fibrosis, which can negatively impact liver function.

Reducing damage by improving function

Cirrhosis causing myofibroblast cells (red) are converted into healthy liver cells (green) to regenerate the damaged liver. (Willenbring lab)

Cirrhosis causing myofibroblast cells (red) are converted into healthy liver cells (green) to regenerate the damaged liver. (Willenbring lab)

In an “Ah-Ha” moment, Willenbring proposed that they could stop myofibroblasts in the damaged livers of mice from causing more fibrosis by turning them into healthy liver cells. Willenbring and his team used a specific type of virus called an adeno-associated virus that only infects myofibroblasts to deliver a cocktail of liver-specific genes that have the ability to transform cells into liver cells called hepatocytes. When they treated mice with end-stage liver disease with their viral cocktail, they observed that a small percentage of myofibroblasts were converted into hepatocytes that developed into new healthy liver tissue, which improved the overall liver function of these mice. They also tested their viral method on human myofibroblasts and found that it was successful in converting these cells into functional hepatocytes.

Willenbring explained the science behind their new technique in a UCSF news release:

“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.”

Solution to a healthy liver?

It’s important to realize that these studies are still in their early stages. The UCSF team has plans to expand on their human cell studies and to improve their viral delivery method so that it is more specific to myofibroblasts and more efficient at converting these cells into functioning hepatocytes.

They also recognize that their strategy will not be the panacea for liver disease and cirrhosis. Willenbring commented:

“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.”

However, their study does offer a number of advantages over cell transplant therapies for liver disease including repairing the liver and improving its function from within the organ itself and also offering a simpler and cheaper form of treatment that would be accessible to more patients.

Willenbring puts it best:

Holger Willenbring, UCSF

Holger Willenbring, UCSF

“The new results suggest that in the fibrotic liver, this approach could produce a more efficient and stable improvement of liver function than cell transplant approaches. Once the viral packaging is optimized, such a treatment could be done cheaply at a broad range of medical facilities, not just in the specialized research hospitals where stem-cell transplants could be conducted.”

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