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
Abstract
AIM

To establish a rat model for evaluating the maturity of liver regeneration derived from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS).

METHODS

In the present study, ALPPS, partial hepatecotmy (PHx), and sham rat models were established initially, which were validated by significant increase of proliferative markers including Ki-67, proliferating cell nuclear antigen, and cyclin D1. In the setting of accelerated proliferation in volume at the second and fifth day after ALPPS, the characteristics of newborn hepatocytes, as well as specific markers of progenitor hepatic cell, were identified. Afterwards, the detection of liver function followed by cluster analysis of functional gene expression were performed to evaluate the maturity.

RESULTS

Compared with PHx and sham groups, the proliferation of FLR was significantly higher in ALPPS group (P = 0.023 and 0.001 at second day, P = 0.034 and P < 0.001 at fifth day after stage I). Meanwhile, the increased expression of proliferative markers including Ki-67, proliferating cell nuclear antigen, and cyclin D1 verified the accelerated liver regeneration derived from ALPPS procedure. However, ALPPS-induced Sox9 positive hepatocytes significantly increased beyond the portal triad, which indicated the progenitor hepatic cell was potentially involved. And the characteristics of ALPPS-induced hepatocytes indicated the lower expression of hepatocyte nuclear factor 4 and anti-tryptase in early proliferative stage. Both suggested the immaturity of ALPPS-derived liver regeneration. Additionally, the detection of liver function and functional genes expression confirmed the immaturity of renascent hepatocytes derived in early stage of ALPPS-derived liver regeneration.

CONCLUSION

Our study revealed the immaturity of ALPPS-derived proliferation in early regenerative response, which indicated that the volumetric assessment overestimated the functional proliferation. This could be convincing evidence that the stage II of ALPPS should be performed prudently in patients with marginally adequate FLR, as the ALPPS-derived proliferation in volume lags behind the functional regeneration.

Keywords: Associating liver partition and portal vein ligation for staged hepatectomy; Liver regeneration; Hepatic progenitor cell; Function; Immature

Core tip: Despite the rapid proliferation of future liver remnant induced by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), the high mortality and morbidity rates have remained alarming. A plausible reason was the functional proliferation lagged behind the increase in volume. In this study, a rat model was established to evaluate the maturity of ALPPS-derived hepatocytes. Through the identification of hepatic characteristics, detection of liver function, and analysis of functional gene expression, we revealed the immaturity of ALPPS-derived proliferation in early regenerative response, which indicated that the volumetric assessment overestimated the functional proliferation. And clinically, the stage II of ALPPS should be performed prudently in patients with marginally adequate FLR, as the ALPPS-derived proliferation in volume lags behind the functional regeneration.