Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Dec 27, 2020; 12(12): 1198-1210
Published online Dec 27, 2020. doi: 10.4254/wjh.v12.i12.1198
Cyclin-dependent kinase inhibitors p21 and p27 function as critical regulators of liver regeneration following 90% hepatectomy in the rat
Nicolas Moniaux, Laurence Lacaze, Adélie Gothland, Alice Deshayes, Didier Samuel, Jamila Faivre
Nicolas Moniaux, Laurence Lacaze, Adélie Gothland, Alice Deshayes, Didier Samuel, Jamila Faivre, INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif 94800, France
Nicolas Moniaux, Laurence Lacaze, Adélie Gothland, Alice Deshayes, Didier Samuel, Jamila Faivre, Université Paris-Saclay, Faculté de Médecine Le Kremlin, Bicêtre 94270, France
Jamila Faivre, Department of Pôle de Biologie Médicale, Laboratoire d’Onco-Hématologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Paul-Brousse University Hospital, Villejuif 94800, France
Author contributions: Moniaux N, Lacaze L, and Gothland A performed most of the experiments and analyzed the data; Deshayes A helped with handling animal tissues and western blot analysis; Faivre J designed the experiments, analyzed the data, and supervised the research; Moniaux N, Faivre J, and Samuel D wrote the manuscript.
Institutional animal care and use committee statement: Animal studies were performed in compliance with the institutional and European Union guidelines for laboratory animal care and approved by the CE2A-03-CNRS-Orléans Ethics Committee (Accreditation No. 01417.01).
Conflict-of-interest statement: All authors declare that they have no conflicts of interest.
Data sharing statement: Technical appendices, statistical codes, and datasets are available from the corresponding author at nicolas.moniaux@inserm.fr. No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared in accordance with them.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Nicolas Moniaux, PhD, Academic Research, Research Scientist, Senior Scientist, INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, 12-14 Ave Paul Vaillant-Couturier, Villejuif 94800, France. nicolas.moniaux@inserm.fr
Received: June 15, 2020
Peer-review started: June 15, 2020
First decision: July 30, 2020
Revised: August 26, 2020
Accepted: October 28, 2020
Article in press: October 28, 2020
Published online: December 27, 2020
Processing time: 185 Days and 15.9 Hours
Abstract
BACKGROUND

Liver reduction is the main curative treatment for primary liver cancer, but its use remains limited as liver regeneration requires a minimum of 30% functional parenchyma.

AIM

To study the dynamics of the liver regeneration process and consequent behavior of cell cycle regulators in rats after extended hepatectomy (90%) and postoperative glucose infusions.

METHODS

Post-hepatectomy liver failure was triggered in 84 Wistar rats by reducing their liver mass by 90%. The animals received a post-operative glucose infusion and were randomly assigned to two groups: One to investigate the survival rate and the other for biochemical analyses. Animals that underwent laparotomy or 70% hepatectomy were used as controls. Blood and liver samples were collected on postoperative days 1 to 7. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, and western blotting.

RESULTS

Postoperative mortality after major resection reached 20% and 55% in the first 24 h and 48 h, respectively, with an overall total of 70% 7 d after surgery. No apparent signs of apoptotic cell death were detected in the extended hepatectomy rat livers, but hepatocytes displaying a clear cytoplasm and an accumulation of hyaline material testified to changes affecting their functional activities. Liver regeneration started properly, as early events initiating cell proliferation occurred within the first 3 h, and the G1 to S transition was detected in less than 12 h. However, a rise in p27 (Kip1) followed by p21 (Waf1/Cip1) cell cycle inhibitor levels led to a delayed S phase progression and mitosis. Overall, liver regeneration in rats with a 90% hepatectomy was delayed by 24 h and associated with a delayed onset and lower peak magnitude of hepatocellular deoxyribonucleic acid synthesis.

CONCLUSION

This work highlights the critical importance of the cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family in regulating the liver regeneration timeline following extended hepatectomy.

Keywords: Major hepatectomy, Liver failure, Liver regeneration, Post-hepatectomy liver failure, p21, p27

Core Tip: There is a current pandemic of obesity and diabetes and the chronic liver damages they cause, and the outcomes of patients undergoing liver mass reduction for malignant diseases are poor. To design efficient strategies that limit the risk of post-hepatectomy liver failure, we used a rat model to clarify the causes of death after enlarged liver resection. Compared with standard 2/3 hepatectomy, enlarged resection resulted in a loss of hepatocyte functional activities and impaired regenerative capacities, which were associated with an overexpression of p21 and p27 inhibitors. The use of extracorporeal support device with p21 and p27 should be considered for the management of severe liver failure following extended hepatectomy.