Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer

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

Research output: Contribution to journalArticlepeer-review

348 Citations (Scopus)


Summary 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.

Original languageEnglish
Pages (from-to)766-779
Number of pages14
Issue number4
Publication statusPublished - 2015 Aug 17
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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