In a demonstration of transdifferentiation, a new study published in Nature shows that hepatocytes in mice can convert to cholangiocytes to build a new functioning biliary system that was absent in development. By elucidating the driver of this mechanism, these findings redefine hepatocyte plasticity and could lead to novel treatments for cholestatic liver diseases.

Previous work by the authors had led to the generation of NOTCH-deficient mice born without intrahepatic bile ducts (IHBD), mimicking a phenotype seen in patients with Alagille syndrome. However, formation of IHBDs was later observed in these mice, prompting an investigation into the cellular origin of the new biliary system using genetic cell fate tracing. “We developed new tools based on the Flp recombinase system to specifically label hepatocytes in the mouse liver,” explains author Holger Willenbring. “We found that hepatocytes can become cholangiocytes that are indistinguishable from primary cholangiocytes.”

Changing cellular identity to replenish missing cells, known as transdifferentiation, has been observed in various other tissues. However, in the latest study, the hepatocyte-derived cholangiocytes formed functional IHBDs without guidance from pre-existing bile ducts. Such de novo formation of mammalian structures from transdifferentiation was previously unknown.

“We also identified the molecular mechanism driving this process,” reports author Stacey Huppert. “In contrast to bile duct development, where NOTCH signalling is essential, we found that TGFβ signalling can compensate in the adult liver.” Furthermore, TGFβ signalling was active in IHBDs found in some patients with Alagille syndrome and could be targeted to enhance the formation of the biliary system from hepatocytes in mice.

“We are now using the understanding and tools generated in our study to develop hepatocyte-transdifferentiation-based strategies for therapy of cholestatic liver diseases,” concludes Willenbring.