Journal
CELL
Volume 162, Issue 4, Pages 766-779Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.07.026
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Funding
- CIRM Training Grant II [TG2-01154]
- Rotary Foundation
- JSPS
- Uehara Memorial Foundation Fellowship
- DFG
- CRI-Irvington fellowship
- Japanese Society of Gastroenterology
- Tokyo Society of Medical Sciences
- Kanae Foundation
- NIH [CA118165, CA155120, HL053670, AI048034, DK078803, DK068471, F32CA136124]
- Superfund basic research program [ES010337]
- Cancer Ctr Core Grant [P30 CA014195-38]
- Frances C. Berger Foundation
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
- JDRF
- Grants-in-Aid for Scientific Research [15K19313] Funding Source: KAKEN
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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.
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