Liver Failure After Extended Hepatectomy in Mice Is Mediated by a p21-Dependent Barrier to Liver Regeneration
Abstract
Background & aims Extended liver resection leads to hepatic failure because of a small remnant liver volume. Excessive parenchymal damage has been proposed as the principal cause of this failure, but little is known about the contribution of a primary deficiency in liver regeneration. We developed a mouse model to assess the regenerative capacity of a critically small liver remnant.Methods Extended (86%) hepatectomy (eHx) was modified to minimize collateral damage; effects were compared with those of standard (68%) partial hepatectomy (pHx) in mice. Markers of liver integrity and survival were evaluated after resection. Liver regeneration was assessed by weight gain, proliferative activity (analyses of Ki67, proliferating cell nuclear antigen, phosphorylated histone 3, mitosis, and ploidy), and regeneration-associated molecules. Knockout mice were used to study the role of p21.Results Compared with pHx, survival of mice was reduced after eHx, and associated with cholestasis and impaired liver function. However, no significant differences in hepatocyte death, sinusoidal injury, oxidative stress, or energy depletion were observed between mice after eHx or pHx. No defect in the initiation of hepatocyte proliferation was apparent. However, restoration of liver mass was delayed after eHx and associated with inadequate induction of Foxm1b and a p21-dependent delay in cell-cycle progression. In p21(-/-) mice, the cell cycle was restored, the gain in liver weight was accelerated, and survival improved after eHx.Conclusions Significant parenchymal injury is not required for liver failure to develop after extended hepatectomy. Rather, liver dysfunction after eHx results from a transient, p21-dependent block before hepatocyte division. Therefore, a deficiency in cell-cycle progression causes liver failure after extended hepatectomy and can be overcome by inhibition of p21.
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p21 deficiency supports tissue regeneration, including complete rescue of regeneration of the impaired liver.
“p21 deficiency supports tissue regeneration, including complete rescue of regeneration of the impaired liver”
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- Authors
- Lehmann, K., Tschuor, C., Rickenbacher, A., Jang, J., Oberkofler, C. E., Tschopp, O., Schultze, S. M., Raptis, D. A., Weber, A., Graf, R., Humar, B., & Clavien, P.
- Affiliations
- University Hospital Zurich (CH)
- Corresponding author
- Clavien, Pierre–Alain
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 143
- Issue
- 6
- Pages
- 1609-1619.e4
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2023465339
- Cited by
- 137
- References
- 27
- Citations by year
- 2025: 3 · 2024: 13 · 2023: 15 · 2022: 7 · 2021: 9 · 2020: 8 · 2019: 12 · 2018: 13 · 2017: 14 · 2016: 11 · 2015: 14 · 2014: 10 · 2013: 8
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Olga Mayenfisch Stiftung
- Universitätsspital Zürich
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (32003B-109906)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- extended hepatectomy, liver failure, liver regeneration, p21, cell cycle progression, FoxM1B, hepatocyte proliferation, partial hepatectomy, cholestasis, mouse model, hepatocyte death
- MeSH terms
- Forkhead Box Protein M1, Animals, Cell Cycle, Disease Models, Animal, Hepatectomy, Liver, Liver Regeneration, Mice, Inbred C57BL, Organ Size, Liver Failure, Mice, Knockout, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Mice, Forkhead Transcription Factors
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