Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer
Open accessAbstract
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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YAP promotes SRY-box transcription factor 9 (SOX9) expression in hepatocytes and may confer the hybrid hepatocyte-biliary identity of periportal SOX9+ hepatocytes.
“However, YAP promotes SRY-box transcription factor 9 (SOX9) expression in hepatocytes59 and may confer the hybrid hepatocyte-biliary identity of periportal SOX9+ hepatocytes.60”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [60]
The Results (‘HybHP Exhibit a Unique Transcriptome’; page unavailable) show that periportal hybrid hepatocytes express SOX9 and have some bile-duct characteristics. But the cited paper does not link YAP to that hybrid identity; the Discussion instead suggests that proximity to ductal cells and factors such as Notch ligands may contribute to their partial ductal character. Citation 59, not this source, is attached to the separate claim that YAP promotes SOX9 expression. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPeriportal hepatocytes do not expand towards zone 3 under homeostatic conditions, and may reduce over time.
“Alternative methods based on tracing of periportal hepatocytes showed that periportal hepatocytes do not expand towards zone 360 under homeostatic conditions, and may reduce over time.84”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [60]
The Results section reports that uninjured littermates did not show expansion of hybrid periportal hepatocytes, supporting the claim that they do not expand toward zone 3 under homeostatic conditions. It does not support a reduction over time: the same section says GFP-positive periportal hepatocytes were stable throughout life and YFP-positive cells remained stable for at least nine months. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredFollowing diverse injuries, often involving cholestasis, YAP signalling drives hepatocyte reprogramming via SOX9 induction.
“Following diverse injuries, often involving cholestasis, YAP signalling also drives hepatocyte reprogramming via SOX9 induction.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [60]
The Results section (“Clonally Labeled HybHP Produce New Hepatocytes and Transdifferentiate into Duct Cells”; page unavailable) reports that pre-existing hybrid hepatocytes acquired strong SOX9 expression and ductal characteristics after cholestatic injury. It does not establish that YAP signalling induces SOX9 or drives this reprogramming, and its cholestatic result does not establish that mechanism across diverse injuries. (LLM, conf=0.84)
Experimental — accuracy not yet measuredReprogrammed zone 1 hepatocytes exhibited reduced metabolic function, upregulated tissue stem cell markers and increased proliferative capacity, contributing to regeneration.
“These reprogrammed zone 1 hepatocytes exhibited reduced metabolic function, upregulated tissue stem cell markers and increased proliferative capacity, contributing to regeneration.59,60,100,101”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [60]
The Results ('HybHP Exhibit a Unique Transcriptome') report lower expression of oxidative drug-metabolism genes and expression of ductal markers including Sox9 and Opn. The Discussion reports that these periportal hepatocytes proliferate to restore liver mass after chronic injury. But the paper describes them as a pre-existing population in healthy liver, not hepatocytes reprogrammed during regeneration; it also does not establish a general reduction in metabolic function or characterize the ductal markers as upregulated tissue stem-cell markers. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLineage-tracing data have shown that hepatocytes in different zones can adopt the gene expression programme of the new zone they reside in.
“Additionally, lineage-tracing data have shown that hepatocytes in the different zones can adopt the gene expression programme of the new zone they reside in.49,60,84,86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [60]
In Results, “Hybrid Periportal Hepatocytes with High Regenerative Capacity” (page unavailable), lineage-traced periportal hepatocyte descendants that reached the central vein expressed a zone 3 marker; the authors say their metabolic profiles matched their locations. This supports a periportal-to-pericentral example, but not the broader claim that hepatocytes from different zones adopt the gene-expression programme of any new zone. The Discussion, “HybHP as Distinct Hepatocyte Subpopulation” (page unavailable), also says it is unknown whether the cells’ transcriptomic profile is determined by location. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Zone 1 SOX9+ hepatocytes next to the bile ducts expanded throughout the lobule, giving rise to large clones when CCl4 was applied repeatedly to damage zone 3 hepatocytes.
“Zone 1 SOX9+ hepatocytes next to the bile ducts expanded throughout the lobule, giving rise to large clones when CCl4 was applied repeatedly to damage zone 3 hepatocytes60”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [60]
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- Authors
- Font-Burgada, J., Shalapour, S., Ramaswamy, S., Hsueh, B., Rossell, D., Umemura, A., Taniguchi, K., Nakagawa, H., Valasek, M. A., Ye, L., Kopp, J. L., Sander, M., Carter, H., Deisseroth, K., Verma, I. M., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- Howard Hughes Medical Institute (US)
- University of Warwick (GB)
- University of British Columbia (CA)
- Corresponding author
- Font-Burgada, Joan
- Karin, Michael
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 162
- Issue
- 4
- Pages
- 766-779
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4545590
- OpenAlex
- W2132886417
- Cited by
- 486
- References
- 9
- Citations by year
- 2026: 15 · 2025: 30 · 2024: 29 · 2023: 44 · 2022: 30 · 2021: 65 · 2020: 67 · 2019: 51 · 2018: 53 · 2017: 38 · 2016: 53 · 2015: 10
- FWCI
- 30.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (15K19313)
- National Heart, Lung, and Blood Institute (HL053670, R01HL053670)
- National Institute of Mental Health (T32MH020016)
- National Cancer Institute (CA155120, F32CA136124, R01CA118165, R01CA155120, CA118165, P30CA014195)
- National Institute of Allergy and Infectious Diseases (R01AI048034, R37AI048034, AI048034)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK078803, DK068471, R01DK078803, R01DK068471)
- National Institute of Neurological Disorders and Stroke (P30NS047101)
- National Institute of Environmental Health Sciences (P42ES010337, ES 010337)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- periportal hepatocytes, liver regeneration, hepatocyte proliferation, hepatocellular carcinoma, chronic liver injury, SOX9, lineage tracing, carcinogenesis, cell therapy, portal triad
- MeSH terms
- Animals, Bile Ducts, Liver, Liver Neoplasms, Regeneration, Cell Transplantation, Hepatocytes, Cell Proliferation, Mice, SOX9 Transcription Factor, Transcriptome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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