Stem cells…eh, who needs them anyway?!

That’s what you might be thinking after today, at least for some forms of liver disease. That’s because a team of researchers from UCSF and Cincinnati Children’s Hospital Medical Center just published results in Nature showing liver cells can directly change identity, or transdifferentiate, to build structures missing due to disease from scratch.

Liver’s regenerative power

The liver’s extraordinary regenerative power in animals is well documented. A human liver, for instance, can fully regrow from just 25% of its original mass.

That’s thanks to the hepatocyte, the main type of liver cell, which can replenish pre-existing tissue lost to disease or injury. Less clear is whether hepatocytes can change identity and build functional liver structures from scratch that never developed in the first place because of genetic disorders.

Alagile syndrome

To examine that possibility, the study, funded in part by CIRM, focused on an inherited liver disease called Alagille syndrome, caused by abnormal bile ducts. Produced by the liver, bile helps digest dietary fats. It travels from the liver via bile ducts, tree–branch–like tube structures in the liver, to the gallbladder, where it’s stored before moving to the small intestine.

In Alagille syndrome, the bile ducts are fewer, narrower, or missing altogether. As a result, the bile builds up in the liver, causing scarring and severe damage. Nearly half of all those with Alagille syndrome require a liver transplant, usually in childhood.

The research team mimicked Alagille syndrome symptoms in mice by genetically engineering the animals to lack cholangiocytes, the cells that form bile ducts. As expected, these mice showed liver damage from bile buildup at birth because they lacked bile duct structures, also called the biliary tree.

However, 90% of the mice survived and eventually formed a functional biliary tree. The team then showed, for the first time, that the hepatocytes converted en masse into cholangiocytes and formed entirely new bile ducts.

Underlying mechanism

The researchers further examined the underlying molecular mechanisms of this process. The researchers showed that the lack of a specific gene-activity pathway, due to the absence of a specific gene, triggers a replacement pathway driven by TGF‑beta. As a result, hepatocytes convert into cholangiocytes and form bile ducts. To link this to the human disease, the team found TGF‑beta activity in liver samples from some patients, but not in healthy livers.

Using this Alagille syndrome mouse model, the researchers aim to identify which transcription factors help convert liver cells into bile duct cells. Holger Willenbring, MD, PhD, a senior author and CIRM grantee, explained the rationale in a press release:

“Rather than developing a stem‑cell therapy in the lab and transplanting it into patients, this approach would stimulate the regenerative capacity of liver cells already in the body.”

If successful in patients with Alagille syndrome—which affects only 1 in 30,000—this strategy could one day apply to other liver diseases as well.