Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer.
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.
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. Electronic address: jfontburgada@ucsd.edu.
Joan
J
Font-Burgada
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.
Shabnam
S
Shalapour
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Suvasini
S
Ramaswamy
Departments of Bioengineering, Psychiatry, and Behavioral Sciences, Neurosciences Program, Howard Hughes Medical Institute, Stanford University, 318 Campus Drive West, Clark Center W080, Stanford, CA 94305, USA.
Brian
B
Hsueh
Department of Statistics, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
David
D
Rossell
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.
Atsushi
A
Umemura
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.
Koji
K
Taniguchi
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; Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655.
Hayato
H
Nakagawa
Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Mark A
MA
Valasek
Departments of Bioengineering, Psychiatry, and Behavioral Sciences, Neurosciences Program, Howard Hughes Medical Institute, Stanford University, 318 Campus Drive West, Clark Center W080, Stanford, CA 94305, USA.
Li
L
Ye
Department of Pediatrics and Department of Cellular & Molecular Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Cellular & Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
Janel L
JL
Kopp
Department of Pediatrics and Department of Cellular & Molecular Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Maike
M
Sander
Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Hannah
H
Carter
Departments of Bioengineering, Psychiatry, and Behavioral Sciences, Neurosciences Program, Howard Hughes Medical Institute, Stanford University, 318 Campus Drive West, Clark Center W080, Stanford, CA 94305, USA.
Karl
K
Deisseroth
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Inder M
IM
Verma
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; Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.
Michael
M
Karin
D000818:Animals; D001652:Bile Ducts / Q000166:cytology; D049109:Cell Proliferation; D017690:Cell Transplantation / Q000379:methods; D022781:Hepatocytes / Q000145:classification / Q000166:cytology / Q000637:transplantation*; D008099:Liver / Q000166:cytology* / Q000293:injuries / Q000502:physiology*; D008113:Liver Neoplasms; D051379:Mice; D012038:Regeneration; D055758:SOX9 Transcription Factor / Q000235:genetics; D059467:Transcriptome
D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse