Nature Article by Willenbring Lab Demonstrates How Liver Cells Switch Identities to Grow New Tissue
In the medieval ages, alchemists dedicated their lifetimes searching for the formula that would transform ordinary metals into gold. In our bodies, several cases of “cellular alchemy” have been reported. Known as transdifferentiation, this process consists of one specialized cell type transmuting into a different one.
Until now, this phenomenon had only been observed in the context of replenishing cells lost from pre-existing structures. Now, UCSF researchers, led by Holger Willenbring, MD, PhD, professor of surgery and associate director of the Liver Center at UCSF, and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, show, for the first time, that transdifferentiation can also occur to generate a structure that failed to be built in development.
The researchers made these findings in a mouse model of Alagille syndrome (ALGS), a rare, inherited genetic disorder where the bile ducts, responsible for delivering bile made in the liver to the intestine, are either not formed or of insufficient diameter. The resulting accumulation of bile in the liver can cause irreparable damage, with 50 percent of patients requiring a liver transplant.
In breakthrough research published May 2, 2018 in the journal Nature, Willenbring and colleagues generated mice lacking Notch signaling required to form biliary ducts during development, and observed that in these mice hepatocytes transdifferentiated into mature cholangiocytes and formed bile ducts that reverse liver damage. These findings change the paradigm in the field, where thus far hepatocytes had only been found to convert into biliary duct cells incompletely and transiently in the context of injury in an adult animal.
In addition to making more of themselves, liver cells can switch their identity to produce a liver cell type that is lost or, in the case of severe ALGS, never formed," said Willenbring who was a senior author of the study and leads the Willenbring Lab at UCSF.
Although the experiments were carried out in mice, they hold great promise for the development of novel therapies for ALGS and other liver disorders.
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," says Willenbring. More specifically, he continued, "using transcription factors to make bile ducts from hepatocytes has potential as a safe and effective therapy. With our finding that an entire biliary system can be 'retrofitted' in the mouse liver, I am encouraged that this eventually will work in patients.
Co-lead authors were Johanna R. Schaub, PhD, and Simone Kurial, of UCSF, as well as Kari A. Huppert, of Cincinnati Children’s Hospital Medical Center. The study was co-led by Willenbring and Stacey Huppert, PhD at Cincinnati Children’s Hospital Medical Center.