Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2017; 23(45): 7978-7988
Published online Dec 7, 2017. doi: 10.3748/wjg.v23.i45.7978
Mesenchymal stem cells rescue acute hepatic failure by polarizing M2 macrophages
Yan-Wei Li, Chong Zhang, Qiu-Ju Sheng, Han Bai, Yang Ding, Xiao-Guang Dou
Yan-Wei Li, Chong Zhang, Qiu-Ju Sheng, Han Bai, Yang Ding, Xiao-Guang Dou, Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
Author contributions: Li YW, Zhang C, Sheng QJ, Bai H, Ding Y, and Dou XG substantially contributed to the conception and design of the study and acquisition, analysis, and interpretation of the data; all authors drafted the article, made critical revisions related to the intellectual content of the manuscript, and approved the final version of the article to be published.
Supported by Liaoning Provincial Science and Technology Key Project for Translational Medicine, No. 2014225020; Outstanding Scientific Fund of Shengjing Hospital, No. 201102; and Liaoning Provincial Science and Technology Key Project for Translational Medicine, No. 2016509.
Institutional review board statement: The study was reviewed and approved by Shengjing Hospital of China Medical University Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Ethics Committee of Shengjing Hospital of China Medical University Institutional. (IACUC protocol number: 2016PS248K).
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.
Data sharing statement: The technical appendix, statistical code and dataset are available from the first author Yan-Wei Li at liyanwei201510296@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: Xiao-Guang Dou, PhD, Chief Doctor, Department of Infectious Diseases, Shengjing Hospital of China Medical University, NO.39 Huaxiang Road, Shenyang 110022, Liaoning Province, China. douxg@sj-hospital.org
Telephone: +86-24-9661562211 Fax: +86-24-25998744
Received: August 31, 2017
Peer-review started: September 3, 2017
First decision: September 20, 2017
Revised: October 1, 2017
Accepted: November 1, 2017
Article in press: November 1, 2017
Published online: December 7, 2017
Processing time: 95 Days and 4.2 Hours
ARTICLE HIGHLIGHTS
Research background

Recent studies have demonstrated that macrophages promote stem cell activity via paracrine action. Macrophages can express multi-phenotype and multi-functional roles in the liver and are a major source of both pro-proliferative and anti-proliferative mediators in liver pathology. There is little information available on the role of macrophage polarization in rescuing acute hepatic failure by mesenchymal stem cells.

Research motivation

Different macrophage phenotypes play various roles in tissue damage and maintenance. It is not clear whether M1 or M2 polarization contributes to the therapeutic effects of mesenchymal stem cells (MSCs). Macrophages to M1 or M2 polarization can increase infused MSCs activity during MSC transplantation, and improve the clinical efficacy of MSCs in the treatment of acute hepatic failure.

Research objectives

To investigate whether M1 or M2 polarization contributes to the therapeutic effects of MSCs.

Research methods

The rats were divided into a survival group and a death group at 48 h after MSC treatment. The rats in the survival group were still in good physical condition at 48 h after MSC treatment. The rats in the death group were in poor physical condition or in the state of death before they died at 48 h after MSC treatment. The polarization of M1 and M2 was compared between the two groups. Macrophage polarization was analyzed by M1 markers [CD68, tumor necrosis factor alpha (TNF-a), interferon-γ (IFN-γ), and inducible nitric oxide synthase (INOS)] and M2 markers [CD163, interleukin (IL)-4, IL-10, and arginase-1 (Arg-1)].

Research results

The number of CD163+ macrophages and levels of IL-4, IL-10, and Arg-1 were significantly up-regulated in the survival group. In contrast, CD68+ macrophages and levels of TFN-γ, TNF-α, and INOS were significantly up-regulated in the death group. However, a specific signaling pathway between macrophage polarization, associated cytokines, and hepatocyte regeneration has not been examined to date.

Research conclusions

This study demonstrates that expression of hepatic progenitor surface marker (EpCAM) is the key to improving the prognosis of AHF. We detected macrophage polarization by cell markers and related cytokines. M2 macrophages play a crucial role in the prognosis of AHF, which results in altered levels of anti-inflammatory and pro-inflammatory factors. The mechanism by which M2 macrophages participate in activation of infused MSCs remains unclear. The observed differential effects of M1 and M2 macrophages suggest that M2 polarization may provide a potential therapeutic application in AHF after MSC transplantation.

Research perspectives

M2 macrophages and their associated cytokines can contribute to AHF rescuing by MSCs. It is unclear whether M2 related cytokines originate from the liver or from the implanted MSCs. Further localization studies and relevant cell experiments are needed to confirm the results.