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Significance Statement
The research team lead by University of California San Diego researchers discovered the main cells responsible for liver regeneration called hybrid hepatocytes found in the portal triad. After chronic liver injury, these unique cells proliferate extensively and replenish liver tissue. While they are similar in many ways to regular hepatocytes, they express far lower levels of bile duct cell-specific genes. hybrid hepatocytes are not stem cells, thus far they seem to be the most effective in rescuing a diseased liver from complete failure. This discovery open the way for new cell-based therapies which may replace the use of liver transplants
Journal Reference
Joan Font-Burgada, Shabnam Shalapour, Suvasini Ramaswamy, Brian Hsueh, David Rossell, Atsushi Umemura, Koji Taniguchi, Hayato Nakagawa, Mark A. Valasek, Li Ye, Janel L. Kopp, Maike Sander, Hannah Carter, Karl Deisseroth, Inder M. Verma, Michael Karin.
Cell, doi: 10.1016/j.cell.2015.07.026, published 13 August 2015
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
ABSTRACT
Compensatory proliferation triggered by hepatocyte loss is required for liver regeneration and maintenance but also promotes development of hepatocellular carcinoma (HCC). Despite extensive investigation, the cells responsible for hepatocyte restoration or HCC development remain poorly characterized. We used genetic lineage tracing to identify cells responsible for hepatocyte replenishment following chronic liver injury and queried their roles in three distinct HCC models. We found that a pre-existing population of periportal hepatocytes, located in the portal triads of healthy livers and expressing low amounts of Sox9 and other bile-duct-enriched genes, undergo extensive proliferation and replenish liver mass after chronic hepatocyte-depleting injuries. Despite their high regenerative potential, these so-called hybrid hepatocytes do not give rise to HCC in chronically injured livers and thus represent a unique way to restore tissue function and avoid tumorigenesis. This specialized set of pre-existing differentiated cells may be highly suitable for cell-based therapy of chronic hepatocyte-depleting disorders.