Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration
Open accessAbstract
Recent evidence has contradicted the prevailing view that homeostasis and regeneration of the adult liver are mediated by self duplication of lineage-restricted hepatocytes and biliary epithelial cells. These new data suggest that liver progenitor cells do not function solely as a backup system in chronic liver injury; rather, they also produce hepatocytes after acute injury and are in fact the main source of new hepatocytes during normal hepatocyte turnover. In addition, other evidence suggests that hepatocytes are capable of lineage conversion, acting as precursors of biliary epithelial cells during biliary injury. To test these concepts, we generated a hepatocyte fate-tracing model based on timed and specific Cre recombinase expression and marker gene activation in all hepatocytes of adult Rosa26 reporter mice with an adenoassociated viral vector. We found that newly formed hepatocytes derived from preexisting hepatocytes in the normal liver and that liver progenitor cells contributed minimally to acute hepatocyte regeneration. Further, we found no evidence that biliary injury induced conversion of hepatocytes into biliary epithelial cells. These results therefore restore the previously prevailing paradigms of liver homeostasis and regeneration. In addition, our new vector system will be a valuable tool for timed, efficient, and specific loop out of floxed sequences in hepatocytes.
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Hepatocytes have a high replicative potential in vivo.
“Hepatocytes have a high replicative potential in vivo3, 4, however hepatocyte isolation is technically demanding, requires cadaveric liver donation, and hepatocytes cannot be expanded effectively in vitro5.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [3]
The liver repopulating capacity of these HPCs in healthy liver is probably negligible.
“Furthermore, the liver repopulating capacity of these cells in a healthy liver is likely insignificant- previous lineage tracing studies have shown no contribution from HPCs to hepatocytes in healthy liver11,44 and hepatocytes are the primary source of regeneration in normal liver homeostasis3.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [3]
Hepatocytes are the main source of regeneration in normal liver homeostasis.
“Furthermore, the liver repopulating capacity of these cells in a healthy liver is likely insignificant- previous lineage tracing studies have shown no contribution from HPCs to hepatocytes in healthy liver11,44 and hepatocytes are the primary source of regeneration in normal liver homeostasis3.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [3]
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- Authors
- Malato, Y., Naqvi, S., Schürmann, N., Ng, R., Wang, B., Zape, J., Kay, M. A., Grimm, D., & Willenbring, H.
- Affiliations
- University of California, San Francisco (US)
- Heidelberg University (DE)
- Stanford University (US)
- Corresponding author
- Willenbring, Holger
- Venue
- Journal of Clinical Investigation
- Published
- 2011-12-01
- Volume
- 121
- Issue
- 12
- Pages
- 4850-4860
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3226005
- OpenAlex
- W2007832228
- Cited by
- 434
- References
- 69
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 17 · 2023: 28 · 2022: 23 · 2021: 32 · 2020: 26 · 2019: 34 · 2018: 50 · 2017: 25 · 2016: 33 · 2015: 33 · 2014: 41 · 2013: 43 · 2012: 19
- FWCI
- 21.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- California Institute for Regenerative Medicine
- University of California, San Francisco (P30DK026743)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK091005, P30DK026743)
- Liver Center, University of California, San Francisco (P30 DK026743)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- liver homeostasis, liver regeneration, liver progenitor cells, hepatocyte turnover, lineage conversion, cholangiocytes, biliary injury, adeno-associated virus vectors, Cre recombinase
- MeSH terms
- Dependovirus, Animals, Bacterial Proteins, Carbon Tetrachloride Poisoning, Epithelial Cells, Genetic Vectors, Hepatectomy, Hepatic Duct, Common, Homeostasis, Liver, Liver Regeneration, Luminescent Proteins, Mice, Inbred C57BL, Prealbumin, Pyridines, Species Specificity, Stem Cells, Genes, Reporter, Cell Lineage, Transgenes, Integrases, Hepatocytes, Mice, Chemical and Drug Induced Liver Injury
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