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
Abstract
AIM

To investigate whether M1 or M2 polarization contributes to the therapeutic effects of mesenchymal stem cells (MSCs) in acute hepatic failure (AHF).

METHODS

MSCs were transfused into rats with AHF induced by D-galactosamine (DGalN). The therapeutic effects of MSCs were evaluated based on survival rate and hepatocyte proliferation and apoptosis. Hepatocyte regeneration capacity was evaluated by the expression of the hepatic progenitor surface marker epithelial cell adhesion molecule (EpCAM). Macrophage polarization was analyzed by M1 markers [CD68, tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ), inducible nitric oxide synthase (INOS)] and M2 markers [CD163, interleukin (IL)-4, IL-10, arginase-1 (Arg-1)] in the survival and death groups after MSC transplantation.

RESULTS

The survival rate in the MSC-treated group was increased compared with the DPBS-treated control group (37.5% vs 10%). MSC treatment protected rats with AHF by reducing apoptotic hepatocytes and promoting hepatocyte regeneration. Immunohistochemical analysis showed that MSC treatment significantly increased the expression of EpCAM compared with the control groups (P < 0.001). Expression of EpCAM in the survival group was significantly up-regulated compared with the death group after MSC transplantation (P = 0.003). Transplantation of MSCs significantly improved the expression of CD163 and increased the gene expression of IL-10 and Arg-1 in the survival group. IL-4 concentrations were significantly increased compared to the death group after MSC transplantation (88.51 ± 24.51 pg/mL vs 34.61 ± 6.6 pg/mL, P < 0.001). In contrast, macrophages showed strong expression of CD68, TNF-α, and INOS in the death group. The concentration of IFN-γ was significantly increased compared to the survival group after MSC transplantation (542.11 ± 51.59 pg/mL vs 104.07 ± 42.80 pg/mL, P < 0.001).

CONCLUSION

M2 polarization contributes to the therapeutic effects of MSCs in AHF by altering levels of anti-inflammatory and pro-inflammatory factors.

Keywords: Acute hepatic failure; Mesenchymal stem cells; Macrophages; Polarization; Inflammation

Core tip: M1 or M2 polarization governs the therapeutic effect of acute hepatic failure (AHF). Mesenchymal stem cells (MSCs) were transfused into rats with AHF induced by galactosamine. It was found that MSCs alleviated the survival rate and biochemical indicators by promoting hepatocyte regeneration. Immunohistochemistry, flow cytometry, and RT-PCR showed that M2 polarization contributes to the rescue of AHF by MSCs in the survival group after MSC transplantation. In addition, in the death group after MSC transplantation, the number of M1 macrophages increased significantly. Our findings suggest that M2 polarization contributes to the rescue of AHF by MSCs, which result in altered levels of anti-inflammatory and pro-inflammatory factors.