Adult Hepatocytes Are Generated by Self-Duplication Rather than Stem Cell Differentiation
Open accessAbstract
The liver is thought to utilize facultative stem cells, also known as "oval cells" or "atypical ductal cells" (ADCs), for regeneration following various types of injury. However, this notion has been based largely on in vitro studies and transplantation models; where lineage tracing has been used, results have been conflicting and effect sizes have been small. Here, we used genetic and nucleoside analog-based tools to mark and track the origin and contribution of various cell populations to liver regeneration in vivo following several ADC-inducing insults. We report that, contrary to prevailing stem-cell-based models of regeneration, virtually all new hepatocytes come from preexisting hepatocytes.
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AAV8-TBG-Cre tail vein injection in adult Egfr Fl/Fl mice leads to >99% Cre-mediated recombination specifically in hepatocytes.
“an approach that leads to >99% Cre-mediated recombination specifically in hepatocytes (Fig. S6I) 62,63”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [62]
The Results section (“Hepatocytes Are Derived from Preexisting Hepatocytes In Vivo”; page unavailable) reports that AAV8-TBG-Cre genetically marked more than 99% of hepatocytes in R26YFP mice, with no labeling of nonhepatocytes. This supports the cited sentence’s efficiency and specificity claim, but the paper does not establish that figure for Egfr Fl/Fl mice or specify tail-vein injection. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFurther experiments in mice have shown that hepatocytes can change into a biliary ductular phenotype and later re-differentiate into hepatocytes.
“Further experiments in mice have shown that hepatocytes can change into a biliary ductular phenotype21, 22 then later re-differentiate into hepatocytes23.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [21]
Using the Krt19CreERTLSLTdTomato lineage tracing model, the degree of hepatocyte formation from ductular cells in the CDE diet and recovery model is limited.
“Using the the Krt19CreERTLSLTdTomato lineage tracing model we found the degree of hepatocyte formation from ductular cells in the CDE diet and recovery model is limited13, 21, 45;”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [21]
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- Authors
- Yanger, K., Knigin, D., Zong, Y., Maggs, L., Gu, G., Akiyama, H., Pikarsky, E., & Stanger, B. Z.
- Affiliations
- University of Pennsylvania (US)
- Hebrew University of Jerusalem (IL)
- Vanderbilt University Medical Center (US)
- Gifu University (JP)
- Corresponding author
- Stanger, Ben Z.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 15
- Issue
- 3
- Pages
- 340-349
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4505916
- OpenAlex
- W1989749181
- Cited by
- 426
- References
- 53
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 20 · 2023: 23 · 2022: 22 · 2021: 34 · 2020: 29 · 2019: 43 · 2018: 61 · 2017: 33 · 2016: 64 · 2015: 53 · 2014: 11
- FWCI
- 29.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK065949, R01DK083355, DK083355, P30DK020593, P30DK050306)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- hepatocyte regeneration, adult hepatocytes, self-replication, oval cells, liver regeneration, stem cell differentiation, lineage tracing
- MeSH terms
- Dependovirus, Adult, Animals, Biliary Tract, Cell Differentiation, Epithelial Cells, Humans, Male, Mice, Inbred C57BL, Stem Cells, Hepatocytes, Cell Proliferation
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