Self-maintenance of zonal hepatocytes during adult homeostasis and their complex plasticity upon distinct liver injuries
Chow Hiang Ang,
Philip Arandjelovic,
Jinming Cheng,
Jicheng Yang,
Fusheng Guo,
Yuanquan Yu,
Sarmilla Nelameham,
Lachlan Whitehead,
Jiangtao Li,
David L. Silver,
Nick Barker,
Jane E. Visvader,
Pierce K.H. Chow,
Gordon K. Smyth,
Yunshun Chen,
David M. Virshup,
Nai Yang Fu
Affiliations
Chow Hiang Ang
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore
Philip Arandjelovic
Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Jinming Cheng
Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Jicheng Yang
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore; Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Fusheng Guo
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore
Yuanquan Yu
HPB Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
Sarmilla Nelameham
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore
Lachlan Whitehead
Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Jiangtao Li
HPB Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
David L. Silver
Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore
Nick Barker
Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A∗STAR), Singapore 138673, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Jane E. Visvader
Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
Pierce K.H. Chow
Surgery Academic-Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore; Department of Hepato-pancreato-biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and National Cancer Centre Singapore, Singapore
Gordon K. Smyth
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia
Yunshun Chen
Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
David M. Virshup
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore
Nai Yang Fu
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore; Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Corresponding author
Summary: Hepatocytes are organized into distinct zonal subsets across the liver lobule, yet their contributions to liver homeostasis and regeneration remain controversial. Here, we developed multiple genetic lineage-tracing mouse models to systematically address this. We found that the liver lobule can be divided into two major zonal and molecular hepatocyte populations marked by Cyp2e1 or Gls2. Pericentral Cyp2e1+ and periportal Gls2+ hepatocytes maintain their own lineage during adult homeostasis, while Cyp2e1+ hepatocytes fuel neonatal liver growth. The Gls2+ and Cyp2e1+ populations can rapidly regenerate one another when one of the populations is severely damaged. Midlobular Ccnd1+ hepatocytes are enriched in the Cyp2e1+ zone in adult liver but have limited contributions to regeneration upon partial hepatectomy and severe pericentral injury. Remarkably, Lgr5+ hepatocytes, a unique Cyp2e1+ subset, contribute significantly to liver replenishment upon periportal injuries. Our findings unravel that zonal hepatocytes mainly self-maintain during homeostasis but exhibit complex plasticity in repair upon injury.
