Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2016; 22(26): 6036-6048
Published online Jul 14, 2016. doi: 10.3748/wjg.v22.i26.6036
Umbilical cord-derived mesenchymal stem cells alleviate liver fibrosis in rats
Ning-Li Chai, Xiao-Bin Zhang, Si-Wen Chen, Ke-Xing Fan, En-Qiang Linghu
Ning-Li Chai, Xiao-Bin Zhang, En-Qiang Linghu, Department of Gastroenterology, PLA General Hospital, Beijing 100853, China
Si-Wen Chen, Department of Gastroenterology, NanLou Clinic, PLA General Hospital, Beijing 100853, China
Ke-Xing Fan, Institute of Oncology, the Second Military Medical University, Shanghai 200433, China
Author contributions: Chai NL performed the majority of experiments and analyzed the data; Zhang XB, Chen SW and Fan KX participated equally in the treatment of animals and completed the paper writing task together; Linghu EQ designed and coordinated the research.
Supported by National Natural Science Foundation of China, No. 81072913.
Institutional review board statement: Our research was performed under the approval of the Local Ethics Committee of Chinese PLA Medical Academy (Beijing China), with permit number 2012-32.
Institutional animal care and use committee statement: All of the procedures were performed according to the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health strictly. Appropriate measures were taken to minimize the animals’ pain or discomfort.
Conflict-of-interest statement: We declare that we have no financial and personal relationships with other people or organizations that could inappropriately influence our work.
Data sharing statement: The technical appendix, statistical code and dataset are available from the first author Ning-Li Chai at csxlily@163.com. All the 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: En-Qiang Linghu, MD, Department of Gastroenterology, PLA General Hospital, No. 28, Fuxing Road, Haidian District, Beijing 100853, China. linghuenqiang@vip.sina.com
Fax: +86-10-66937485
Received: January 14, 2016
Peer-review started: January 18, 2016
First decision: March 7, 2016
Revised: April 16, 2016
Accepted: May 23, 2016
Article in press: May 23, 2016
Published online: July 14, 2016
Processing time: 174 Days and 16.8 Hours
Abstract

AIM: To evaluate the efficacy of umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation in the treatment of liver fibrosis.

METHODS: Cultured human UC-MSCs were isolated and transfused into rats with liver fibrosis induced by dimethylnitrosamine (DMN). The effects of UC-MSCs transfusion on liver fibrosis were then evaluated by histopathology; serum interleukin (IL)-4 and IL-10 levels were also measured. Furthermore, Kupffer cells (KCs) in fibrotic livers were isolated and cultured to analyze their phenotype. Moreover, UC-MSCs were co-cultured with KCs in vitro to assess the effects of UC-MSCs on KCs’ phenotype, and IL-4 and IL-10 levels were measured in cell culture supernatants. Finally, UC-MSCs and KCs were cultured in the presence of IL-4 antibodies to block the effects of this cytokine, followed by phenotypical analysis of KCs.

RESULTS: UC-MSCs transfused into rats were recruited by the injured liver and alleviated liver fibrosis, increasing serum IL-4 and IL-10 levels. Interestingly, UC-MSCs promoted mobilization of KCs not only in fibrotic livers, but also in vitro. Co-culture of UC-MSCs with KCs resulted in increased production of IL-4 and IL-10. The addition of IL-4 antibodies into the co-culture system resulted in decreased KC mobilization.

CONCLUSION: UC-MSCs could increase IL-4 and promote mobilization of KCs both in vitro and in vivo, subsequently alleviating the liver fibrosis induced by DMN.

Keywords: Liver fibrosis; Mesenchymal stem cells; Kupffer cells; Interleukin-4; Dimethylnitrosamine; DMN

Core tip: Dysregulation of the M1/M2 macrophages phenotypic balance governs the pathogenesis of liver fibrosis. Flow cytometry, immunohistochemistry and liver function tests showed that umbilical cord-derived mesenchymal stem cells (UC-MSCs) could promote the mobilization of M1 Kupffer cells (KCs) into the M2 phenotype in vivo and in vitro thereby ameliorating liver inflammation and liver fibrosis. Thus, UC-MSC transfusion yielded promising results with regard to reversal of liver injury and alleviated liver fibrosis by promoting KC mobilization and hepatocyte differentiation. The application of UC-MSCs might provide a new tool for cell therapy of liver fibrosis.