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Cellular identity crisis
The liver is already a unique organ, given its ability to regenerate from damage rather than simply forming scar tissue, but recent findings from a team of UC San Francisco and Cincinnati Children’s Hospital Medical Center researchers have revealed that not only can it regenerate, it can order its cells to change identities to replace missing cell types. Their research was published in Nature in a paper titled “De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation.”
This discovery came about due to work with mouse models of Alagille syndrome (ALGS), a rare, inherited genetic disorder characterized by deficiencies in the Notch pathway. Individuals with Alagille syndrome can present with bile ducts that are too few or too narrow, or with a lack of bile ducts in the liver entirely. Without sufficient ducts to carry bile to the intestines, where it aids with digestion of fats, bile gets back up in the liver and damages the organ, leading to a need for organ transplant in up to 50 percent of Alagille patients, according to a UCSF press release.
This newly discovered method of switching identities could offer new hope for such patients, as it makes it possible for liver cells to change their nature to help form tubes to expand bile ducts.
“Previous research has detected adaptive reprogramming in other organs, but it typically involves only a few cells at a time. Our study shows that cells switch their identity at a massive rate in the liver,” said Kari Huppert from Cincinnati Children’s, co-first author.
Dr. Johanna Schaub and Simone Kurial from UCSF were also co-first authors on this work.
The team worked with mice engineered to lack cholangiocytes, the liver cells that form bile ducts. As with cases of severe ALGS, the mice presented with signs of liver injury—symptoms that eventually improved as hepatocytes were converted into cholangiocytes and proceeded to form functional bile ducts. In addition, their work found that the Notch pathway, which plays a pivotal role in the formation of bile ducts and is defective in ALGS patients, can be replaced by another pathway. The substance transforming growth factor beta (TGFβ) is responsible for regulating the process, and the paper notes that “TGFβ signalling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodelling capacity of the bile-duct-deficient liver can be harnessed with transplanted hepatocytes.”
“Our study shows that the form and function of hepatocytes – the cell type that provides most of the liver’s functions – are remarkably flexible. This flexibility provides an opportunity for therapy for a large group of liver diseases,” said UCSF’s Dr. Holger Willenbring, a senior author of the study and a professor in the Department of Surgery. Willenbring is also a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and the Liver Center at UCSF.
As the authors explain in the paper, “Transdifferentiation is a complete and stable change in cell identity that serves as an alternative to stem-cell-mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to the replenishment of cells lost from preexisting structures, in the presence of a fully developed scaffold and niche … These findings redefine hepatocyte plasticity, which appeared to be limited to metaplasia, that is, incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system.”
Though the identification of TGFβ answers some questions about the exact transcription factors that trigger the identity switch in cells, the team is working to uncover what other proteins play a role in this process.
This work sheds new light on research from UCSF back in 2012, which also included Willenbring. A team of UCSF scientists found evidence that the ability of liver cells to switch identities plays a role in cholangiocarcinoma, a rare and deadly type of liver cancer known as bile duct cancer. Prior to this research, it was believed that hepatocellular carcinomas originated in hepatocytes, while cholangiocarcinomas originated in the biliary cells, as noted in a press release penned by UCSF's Jennifer O'Brien.
The discovery came about when Dr. Xin Chen, an assistant professor of bioengineering and therapeutic sciences and a senior author of the study, tried to trigger hepatocytes to induce hepatocellular carcinoma via the activation of oncogenes. Instead, the mice used presented with cholangiocarcinoma.
The NOTCH gene, which plays a role in both the embryonic development of bile ducts and the ability of liver cells to switch identities, was highlighted as one of the suspects for reprogramming hepatocytes and triggering cancer, as was AKT. When plasmids were injected into mice to boost NOTCH and AKT levels, tumors had spread throughout the liver by five weeks. The lab applied previous work in labeling mouse hepatocytes and were able to determine that the bile duct tumors were comprised of cells that had originally been hepatocytes. This work was published in the July 16, 2012, online edition of the Journal of Clinical Investigation.