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Updated: Jun 27, 2026
Isolation of Regenerating Hepatocytes after Partial Hepatectomy in Mice
Published on: December 2, 2022
Hepatocyte-specific deletion of Cdc42 results in delayed liver regeneration after partial hepatectomy in mice
Haixin Yuan1, Hong Zhang, Xunwei Wu
1State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Unlabelled:
Cdc42, a member of the Rho guanosine triphosphatase (GTPase) family, plays important roles in the regulation of the cytoskeleton, cell proliferation, cell polarity, and cellular transport, but little is known about its specific function in mammalian liver. We investigated the function of Cdc42 in regulating liver regeneration. Using a mouse model with liver-specific knockout of Cdc42 (Cdc42LK), we studied liver regeneration after partial hepatectomy. Histological analysis, immunostaining, and western blot analysis were performed to characterize Cdc42LK livers and to explore the role of Cdc42 in liver regeneration. In control mouse livers, Cdc42 became activated between 3 and 24 hours after partial hepatectomy. Loss of Cdc42 led to a significant delay of liver recovery after partial hepatectomy, which was associated with reduced and delayed DNA synthesis indicated by 5-bromo-2'-deoxyuridine staining. Consistent with this, expression of cyclins D1, A, and E was markedly delayed or reduced in Cdc42LK livers during regeneration. As a potential effector of Cdc42, Rac1 activation was dramatically attenuated in Cdc42LK livers after partial hepatectomy, suggesting it is regulated in a Cdc42-dependent manner. Activation of certain proliferative signaling pathways, such as extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p70S6 kinase pathways, was delayed in Cdc42LK livers. In addition, dilated bile canaliculi and excessive lipid accumulation were observed in mutant livers during liver regeneration, which may result from impaired cytoskeletal organization and intracellular trafficking in hepatocytes.
Conclusion:
Our results revealed important roles of Cdc42 in the regulation of proliferative signaling during liver regeneration.
Insights
Cdc42 (a Rho GTPase) is crucial for liver regeneration. Its absence delays DNA synthesis, cyclin expression, and signaling pathways, impairing liver recovery and causing bile duct issues.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Biology
Background:
- Cdc42, a Rho GTPase, regulates cytoskeleton, cell proliferation, and polarity.
- Its specific role in mammalian liver regeneration remains largely unknown.
Purpose of the Study:
- To investigate the function of Cdc42 in regulating liver regeneration.
- To elucidate the molecular mechanisms underlying Cdc42's role in hepatic recovery.
Main Methods:
- Utilized a liver-specific Cdc42 knockout (Cdc42LK) mouse model.
- Analyzed liver regeneration post-partial hepatectomy using histology, immunostaining, and Western blot.
- Assessed DNA synthesis, cyclin expression, and key signaling pathway activation.
Main Results:
- Cdc42 activation peaks 3-24 hours post-hepatectomy in control livers.
- Cdc42LK mice exhibited delayed liver recovery, reduced DNA synthesis, and delayed cyclin expression.
- Rac1 activation, ERK, JNK, and p70S6K pathways were attenuated in Cdc42LK livers.
- Mutant livers showed dilated bile canaliculi and lipid accumulation, suggesting impaired cytoskeletal organization and trafficking.
Conclusions:
- Cdc42 plays a vital role in regulating proliferative signaling pathways during liver regeneration.
- Cdc42 is essential for timely hepatocyte proliferation and restoration of liver function post-injury.
