Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2018; 24(10): 1107-1119
Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1107
Maturity of associating liver partition and portal vein ligation for staged hepatectomy-derived liver regeneration in a rat model
Yi-Fan Tong, Ning Meng, Miao-Qin Chen, Han-Ning Ying, Ming Xu, Billy Lu, Jun-Jie Hong, Yi-Fan Wang, Xiu-Jun Cai
Yi-Fan Tong, Ning Meng, Han-Ning Ying, Ming Xu, Jun-Jie Hong, Yi-Fan Wang, Xiu-Jun Cai, Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
Ning Meng, Department of General Surgery, Second Hospital, School of Medicine, Hangzhou Normal University, Hangzhou 310000, Zhejiang Province, China
Miao-Qin Chen, Department of Biological Treatment Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
Billy Lu, National Center for Advancing Translational Science/National Institutes of Health (NIH), Rickville 20850, American Samoa
Author contributions: Tong YF, Meng N, Chen MQ, Ying HN and Xu M contributed equally to this work; Cai XJ, Wang YF and Tong YF designed research; Tong YF, Chen MQ and Xu M performed research; Meng N and Ying HN contributed new reagents or analytic tools; Tong YF and Chen MQ analyzed data; Tong YF and Meng N wrote the paper; Lu B, Hong JJ and Cai XJ revised and supervised the study and revised the paper; all authors have read and approved the final version to be published.
Supported by the Major Scientific and Technological Project of Zhejiang Province, China, No. 2015C03026.
Institutional review board statement: This study was reviewed and approved by the Ethical Committees for Human Subjects at Zhejiang University, China, Institutional Review Board.
Institutional animal care and use committee statement: All animal experiments were conducted in accordance with policies of Institutional Animal Care and Use Committee (IACUC) of the School of Medicine, Zhejiang University, China. Specific protocols used in this study were approved by School of Medicine, Zhejiang University IACUC.
Conflict-of-interest statement: The authors declared no conflicts of interest was included in the study.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at srrsh_cxj@zju.edu.cn. Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Xiu-Jun Cai, FRSC, MD, Professor, Surgeon, Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Qingchun East Road No.3, Hangzhou 310016, Zhejiang Province, China. srrsh_cxj@zju.edu.cn
Telephone: +86-571-86006605 Fax: +86-571-86006605
Received: December 28, 2017
Peer-review started: December 29, 2017
First decision: January 17, 2018
Revised: February 4, 2018
Accepted: February 9, 2018
Article in press: February 9, 2018
Published online: March 14, 2018
Processing time: 75 Days and 2.9 Hours
ARTICLE HIGHLIGHTS
Research background

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been increasingly popular worldwide recently. However, the high mortality makes surgeons reconsider the difference between functional and volumetric proliferation in ALPPS-derived liver regeneration. In this study, we therefore establish a rat model to mimic the ALPPS, exploring whether the functional proliferation lags behind the hypertrophy in volume.

Research motivation

This was a preliminary study with regard to the maturity of ALPPS-derived liver regeneration. On the basis of developing a rat model, we found the volumetric assessment overestimated the functional proliferation in ALPPS procedure, which indicated the stage II of ALPPS should be performed prudently in patients with marginally adequate future liver remnant.

Research objectives

This study was to evaluate the maturity of ALPPS-derived liver regeneration. In our rat model, the postponed maturity in function might be an important reason for high mortality of ALPPS even when the adequate future liver remnant was achieved before stage II of ALPPS. Likewise, the functional proliferation should be performed to time the stage II of ALPPS clinically.

Research methods

In this study, ALPPS, partial hepatectomy (PHx) and sham models were conducted. The ratio of right middle lobe to body weight as well as proliferative markers were used for assessing the liver regeneration. Morphological changes by HE stain and detection of specific markers of progenitor or mature hepatocytes were adopted to identify the characteristics of newborn hepatocytes. Eventually, the liver function in vivo and vitro was measured, followed by the cluster analysis of expression of functional genes to detect the maturity of liver regeneration from different models.

Research results

By establishment of ALPPS, PHx and sham models, we demonstrated that ALPPS could induce an accelerated proliferative response. However, the characteristics of newborn hepatocytes seemed to be not mature completely. Sox9 positive hepatocyte, as well as different expression of other specific markers, indicated the potential role of progenitor hepatic cell in ALPPS-derived regeneration. Parts of limited liver function and different expression of functional genes supported the above-mentioned immaturity in ALPPS-induced proliferation.

Research conclusions

As the mortality remains unsatisfactory even in patients with adequate future liver remnant after stage I of ALPPS, this study presented the immaturity of ALPPS-derived proliferation in early regenerative response, which indicated that the volumetric assessment overestimated the functional proliferation. To the best of our knowledge, this is the first study to evaluate the maturity of ALPPS-derived liver regeneration in a rat model. Meanwhile, Sox9 positive hepatocyte indicated the potential role of hepatic progenitor cell in the ALPPS rather than conventional PHx model. Therefore, a more detailed research about the hepatic progenitor cell promotes the ALPPS-derived liver regeneration and its mechanism would be done in our next work.

Research perspectives

The stage II of ALPPS should be performed prudently in patients with marginally adequate future liver remnant, as the ALPPS-derived proliferation in volume lags behind the functional regeneration. By the way, as the hepatic progenitor cell might be an important role in ALPPS-derived liver regeneration, our future work is to further demonstrate the fate of Sox9 positive hepatocyte with ALPPS procedure and its underlying mechanism by lineage tracing method.