Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 21, 2017; 23(19): 3449-3467
Published online May 21, 2017. doi: 10.3748/wjg.v23.i19.3449
Effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells on microcirculation and energy metabolism following liver transplantation
Liu Yang, Zhong-Yang Shen, Rao-Rao Wang, Ming-Li Yin, Wei-Ping Zheng, Bin Wu, Tao Liu, Hong-Li Song
Liu Yang, Rao-Rao Wang, Ming-Li Yin, the First Central Clinical College Tianjin Medical University, Tianjin 300070, China
Zhong-Yang Shen, Wei-Ping Zheng, Bin Wu, Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, China
Tao Liu, Tianjin First Central Hospital and Key Laboratory of Emergency and Care Medicine of Ministry of Health, Tianjin 300192, China
Hong-Li Song, Department of Organ Transplantation, Tianjin First Central Hospital and Tianjin Key Laboratory of Organ Transplantation, Tianjin 300192, China
Author contributions: Yang L and Shen ZY contributed equally to this work; Yang L and Shen ZY performed the research, analyzed the data, and wrote and revised the paper; Yang L, Wang RR, Yin ML, Zheng WP, Wu B and Liu T performed the research; Shen ZY participated in research design; Song HL designed the research, participated in the data analysis and revised the paper. All authors have read and approved the final version of the manuscript.
Supported by The National Natural Science Foundation of China, No. 81670574, No. 81441022 and No. 81270528; The Natural Science Foundation of Tianjin, China, No. 08JCYBJC08400, No. 11JCZDJC27800, and No. 12JCZDJC25200; and the Technology Foundation of the Health Bureau in Tianjin, China, No. 2011KY11.
Institutional review board statement: The experimental study has been reviewed and approved by the Institutional Review Committee of Tianjin First Central Hospital, Tianjin, China.
Institutional animal care and use committee statement: All experimental were performed in accordance with the “Guide for the Care and Use of Laboratory Animals” (National Institutes of Health, 8th ed. 2011). All protocols were approved by the Animal Care and Research Committee of Tianjin First Central Hospital. Animals were anaesthetised and exsanguinated for tissue collection.
Conflict-of-interest statement: All authors declare they have no actual or potential competing financial interest related to this study.
Data sharing statement: No additional data are available.
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:
Correspondence to: Hong-Li Song, MD, PhD, Professor of Medicine, Department of Organ Transplantation, Tianjin First Central Hospital and Tianjin Key Laboratory of Organ Transplantation, No. 24 Fukang Road, Nankai District, Tianjin 300192, China.
Telephone: +86-22-23626928 Fax: +86-22-23626622
Received: December 8, 2016
Peer-review started: December 9, 2016
First decision: January 19, 2017
Revised: January 23, 2017
Accepted: February 17, 2017
Article in press: February 17, 2017
Published online: May 21, 2017

To investigate the effects of heme oxygenase-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation (RLT) in a rat model.


BMMSCs were isolated and cultured in vitro using an adherent method, and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs. A rat acute rejection model following 50% RLT was established using a two-cuff technique. Recipients were divided into three groups based on the treatment received: normal saline (NS), BMMSCs and HO-1/BMMSCs. Liver function was examined at six time points. The levels of endothelin-1 (ET-1), endothelial nitric-oxide synthase (eNOS), inducible nitric-oxide synthase (iNOS), nitric oxide (NO), and hyaluronic acid (HA) were detected using an enzyme-linked immunosorbent assay. The portal vein pressure (PVP) was detected by Power Lab ML880. The expressions of ET-1, iNOS, eNOS, and von Willebrand factor (vWF) protein in the transplanted liver were detected using immunohistochemistry and Western blotting. ATPase in the transplanted liver was detected by chemical colorimetry, and the ultrastructural changes were observed under a transmission electron microscope.


HO-1/BMMSCs could alleviate the pathological changes and rejection activity index of the transplanted liver, and improve the liver function of rats following 50% RLT, with statistically significant differences compared with those of the NS group and BMMSCs group (P < 0.05). In term of the microcirculation of hepatic sinusoids: The PVP on POD7 decreased significantly in the HO-1/BMMSCs and BMMSCs groups compared with that of the NS group (P < 0.01); HO-1/BMMSCs could inhibit the expressions of ET-1 and iNOS, increase the expressions of eNOS and inhibit amounts of NO production, and maintain the equilibrium of ET-1/NO (P < 0.05); and HO-1/BMMSCs increased the expression of vWF in hepatic sinusoidal endothelial cells (SECs), and promoted the degradation of HA, compared with those of the NS group and BMMSCs group (P < 0.05). In term of the energy metabolism of the transplanted liver, HO-1/BMMSCs repaired the damaged mitochondria, and improved the activity of mitochondrial aspartate aminotransferase (ASTm) and ATPase, compared with the other two groups (P <0.05).


HO-1/BMMSCs can improve the microcirculation of hepatic sinusoids significantly, and recover the energy metabolism of damaged hepatocytes in rats following RLT, thus protecting the transplanted liver.

Keywords: Reduced-size liver transplantation, Bone marrow mesenchymal stem cells, Microcirculation, Heme oxygenase-1, Energy metabolism

Core tip: Hepatic sinus is important in the liver microcirculation, which is the basis for transplanted liver regeneration. Transplanted liver grafts with disturbed microcirculation of the hepatic sinus may affect liver energy metabolism. We investigated the protective effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) on rat reduced-size liver transplantation in terms of the microcirculation and hepatic energy metabolism. HO-1/BMMSCs promoted the equilibrium of ET-1/NO, repaired damaged hepatic sinusoidal endothelial cells, and lowered the portal vein pressure in rats following reduced-size liver transplantation, which improved the microcirculation of hepatic sinusoids and ATPase activity, and recover the energy metabolism of damaged hepatocytes.