It’s well known that the liver is a regeneration champion. It is one of the few internal organs that can strongly regenerate after injury.
Regenerative liver cells
Other organs, like the heart and lungs, cannot do this and instead form scar tissue to protect damaged areas. Liver regeneration is essential for human health because the liver performs many critical jobs, including making proteins, breaking down toxins, and producing chemicals needed for digestion.
Over the years, scientists have proposed several theories to explain the liver’s remarkable ability to regenerate. What we do know is that mature hepatocytes—the liver’s main cell type—respond to injury by dividing and producing more hepatocytes. This allows the liver to regrow up to 70 percent of its mass within a few weeks. Pretty amazing, right?
So where do these regenerative hepatocytes come from? For a long time, researchers believed adult liver stem cells, called oval cells, were the source. But recent studies have disproved that idea. The answer to this long‑standing question may come from a study published last week in Cell.
Hybrid hepatocytes
A UCSD team led by Dr. Michael Karin has identified a new population of liver cells called “hybrid hepatocytes.” The group discovered these cells in the portal triad of healthy liver tissue. Using mouse models, the CIRM‑funded researchers found that hybrid hepatocytes rapidly divide after chemical injury to replace damaged or lost liver cells. When they examined the cells more closely, they saw that hybrid hepatocytes resemble normal hepatocytes but differ slightly in the liver genes they express.
A major concern with regenerative cells is cancer risk. Actively dividing liver cells can accumulate genetic mutations that lead to 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.
Cirrhosis
Currently, liver transplantation is the only treatment for end‑stage liver disease—often caused by cirrhosis or hepatitis—and for aggressive liver cancers. Patients who receive donor livers generally survive, but donated organs are scarce. Those who do receive transplants must take lifelong immunosuppressant drugs. Stem‑cell‑derived liver tissue, created from embryonic stem cells or induced pluripotent stem cells (iPSCs), has been proposed as an alternative source. However, safety concerns remain, especially the risk that immature iPSCs could form tumors.
This study offers hope for future cell‑based therapies for liver disease while avoiding the challenges associated with iPSC‑derived tissues. In a UCSD press release, Dr. Karin summarized the promise of these 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:
“I’m excited to share that work funded through the CIRM training program will be published in Cell. I am deeply grateful for the opportunity I was given. I’m convinced that without CIRM’s support, I could not have finished my project. The training was excellent, and the resources I received gave me the independence to explore new directions that ultimately led to this publication.”
We at CIRM are always proud to hear about these success stories. Even more important, we value feedback from our grantees about how our funding and training have supported their work and helped them reach their goals. Our mission is to develop stem cell therapies for patients with unmet medical needs, and studies like this show we are making real progress toward that goal.