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.”

New Regenerative Liver Cells Identified

It’s common knowledge that your liver is a champion when it comes to regeneration. It’s actually one of the few internal organs in the human body that can robustly regenerate itself after injury. Other organs such as the heart and lungs do not have the same regenerative response and instead generate scar tissue to protect the injured area. Liver regeneration is very important to human health as the liver conducts many fundamental processes such as making proteins, breaking down toxic substances, and making new chemicals required to digest your food.

The human liver.

The human liver

Over the years, scientists have suggested multiple theories for why the liver has this amazing regenerative capacity. What’s known for sure is that mature hepatocytes (the main cell type in the liver) will respond to injury by dividing and proliferating to make more hepatocytes. In this way, the liver can regrow up to 70% of itself within a matter of a few weeks. Pretty amazing right?

So what is the source of these regenerative hepatocytes? It was originally thought that adult liver stem cells (called oval cells) were the source, but this theory has been disproved in the past few years. The answer to this million-dollar question, however, likely comes from a study published last week in the journal Cell.

Hybrid hepatocytes (shown in green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

Hybrid hepatocytes (green) divide and regenerate the liver in response to injury. (Image source: Font-Burgada et al., 2015)

A group at UCSD led by Dr. Michael Karin reported a new population of liver cells called “hybrid hepatocytes”. These cells were discovered in an area of the healthy liver called the portal triad. Using mouse models, the CIRM-funded group found that hybrid hepatocytes respond to chemical-induced injury by massively dividing to replace damaged or lost liver tissue. When they took a closer look at these newly-identified cells, they found that hybrid hepatocytes were very similar to normal hepatocytes but differed slightly with respect to the types of liver genes that they expressed.

A common concern associated with regenerative tissue and cells is the development of cancer. Actively dividing cells in the liver can acquire genetic mutations that can cause hepatocellular carcinoma, a common form of liver cancer.

What makes this group’s discovery so exciting is that they found evidence that hybrid hepatocytes do not cause cancer in mice. They showed this by transplanting a population of hybrid hepatocytes into multiple mouse models of liver cancer. When they dissected the liver tumors from these mice, none of the transplanted hybrid cells were present. They concluded that hybrid hepatocytes are robust and efficient at regenerating the liver in response to injury, and that they are a safe and non-cancer causing source of regenerating liver cells.

Currently, liver transplantation is the only therapy for end-stage liver diseases (often caused by cirrhosis or hepatitis) and aggressive forms of liver cancer. Patients receiving liver transplants from donors have a good chance of survival, however donated livers are in short supply, and patients who actually get liver transplants have to take immunosuppressant drugs for the rest of their lives. Stem cell-derived liver tissue, either from embryonic or induced pluripotent stem cells (iPSC), has been proposed as an alternative source of transplantable liver tissue. However, safety of iPSC-derived tissue for clinical applications is still being addressed due to the potential risk of tumor formation caused by iPSCs that haven’t fully matured.

This study gives hope to the future of cell-based therapies for liver disease and avoids the current hurdles associated with iPSC-based therapy. In a press release from UCSD, Dr. Karin succinctly summarized the implications of their findings.

“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.”

This exciting and potentially game-changing research was supported by CIRM funding. The first author, Dr. Joan Font-Burgada, was a CIRM postdoctoral scholar from 2012-2014. He reached out to CIRM regarding his publication and provided the following feedback:

CIRM Postdoctoral Fellow Jean Font-Burgada

CIRM postdoctoral scholar Joan Font-Burgada

“I’m excited to let you know that work CIRM funded through the training program will be published in Cell. I would like to express my most sincere gratitude for the opportunity I was given. I am convinced that without CIRM support, I could not have finished my project. Not only the training was excellent but the resources I was offered allowed me to work with enough independence to explore new avenues in my project that finally ended up in this publication.”

 

We at CIRM are always thrilled and proud to hear about these success stories. More importantly, we value feedback from our grantees on how our funding and training has supported their science and helped them achieve their goals. Our mission is to develop stem cell therapies for patients with unmet medical needs, and studies such as this one are an encouraging sign that we are making progress towards to achieving this goal.


Related links:

UCSD Press Release

CIRM Spotlight on Liver Disease Research

CIRM Spotlight on Living with Liver Disease