Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2017; 23(22): 4016-4038
Published online Jun 14, 2017. doi: 10.3748/wjg.v23.i22.4016
Effect of CXCR3/HO-1 genes modified bone marrow mesenchymal stem cells on small bowel transplant rejection
Ming-Li Yin, Hong-Li Song, Yang Yang, Wei-Ping Zheng, Tao Liu, Zhong-Yang Shen
Ming-Li Yin, Tianjin First Central Hospital Clinic Institute, Tianjin Medical University, Tianjin 300070, China
Hong-Li Song, Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin Clinical Research Center for Organ Transplantation and Tianjin Key Laboratory of Organ Transplantation, Tianjin 300192, China
Yang Yang, Wei-Ping Zheng, Zhong-Yang Shen, 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
Author contributions: Yin ML, Song HL and Yang Y performed the research, analyzed the data, and wrote and revised the paper; Yin ML, Yang Y, Zheng WP and Liu T performed the research; Song HL participated in research design; Shen ZY designed the research and participated in the revision of the paper; all authors have read and approved the final 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 of Tianjin, China, No. 2011KY11.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Tianjin First Central Hospital.
Institutional animal care and use committee statement: All experiment on animals were performed in accordance with the “Guide for the Care and Use of Laboratory Animals” (National Institutes of Health, 8th ed. 2011). All procedures involving animals were reviewed and approved by the Animal Care and Research Committee of Tianjin First Central Hospital.
Conflict-of-interest statement: The authors declare no potential conflict of interest for this paper.
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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Zhong-Yang Shen, MD, PhD, Professor, Department of Organ Transplantation, Tianjin First Central Hospital, No. 24 Fukang Road, Nankai District, Tianjin 300192, China. shenzhy@tmu.edu.cn
Telephone: +86-22-2362698 Fax: +86-22-2362698
Received: January 5, 2017
Peer-review started: January 9, 2017
First decision: March 3, 2017
Revised: March 20, 2017
Accepted: May 4, 2017
Article in press: May 4, 2017
Published online: June 14, 2017
Abstract
AIM

To investigate whether bone marrow mesenchymal stem cells (BMMSCs) modified with the HO-1 and CXCR3 genes can augment the inhibitory effect of BMMSCs on small bowel transplant rejection.

METHODS

Lewis rat BMMSCs were cultured in vitro. Third-passage BMMSCs were transduced with the CXCR3/HO-1 genes or the HO-1 gene alone. The rats were divided into six groups and rats in the experimental group were pretreated with BMMSCs 7 d prior to small bowel transplant. Six time points (instant, 1 d, 3 d, 7 d, 10 d, and 14 d) (n = 6) were chosen for each group. Hematoxylin-eosin staining was used to observe pathologic rejection, while immunohistochemistry and Western blot were used to detect protein expression. Flow cytometry was used to detect T lymphocytes and enzyme linked immunosorbent assay was used to detect cytokines.

RESULTS

The median survival time of BMMSCs from the CXCR3/HO-1 modified group (53 d) was significantly longer than that of the HO-1 modified BMMSCs group (39 d), the BMMSCs group (26 d), and the NS group (control group) (16 d) (P < 0.05). Compared with BMMSCs from the HO-1 modified BMMSCs, BMMSCs, and NS groups, rejection of the small bowel in the CXCR3/HO-1 modified group was significantly reduced, while the weight of transplant recipients was also significantly decreased (P < 0.05). Furthermore, IL-2, IL-6, IL-17, IFN-γ, and TNF-α levels were significantly decreased and the levels of IL-10 and TGF-β were significantly increased (P < 0.05).

CONCLUSION

BMMSCs modified with the CXCR3 and HO-1 genes can abrogate the rejection of transplanted small bowel more effectively and significantly increase the survival time of rats that receive a small bowel transplant.

Keywords: Bone marrow mesenchymal stem cells, CXCR3, HO-1, Small bowel transplantation, Rejection

Core tip: In this paper, transplant recipient rats were pretreated with bone marrow mesenchymal stem cells (BMMSCs) in advance, and these rats were in a compromised immune state. CXCR3/HO-1 gene modified BMMSCs were injected into recipient rats after small bowel transplantation. The survival time of these rats was significantly prolonged; the number of cells that underwent apoptosis was significantly lower in the CXCR3/HO-1 modified BMMSCs group compared with rats from the HO-1 gene modified BMMSCs group, the native BMMSCs group, and the NS group. Furthermore, the percentage of regulatory T cells was significantly increased. Proinflammatory cytokines (IL-2, IL-6, IL-17, IFN-γ, and TNF-α) were significantly reduced, while anti-inflammatory cytokines (IL-10 and TGF-β) were significantly increased. Our data suggest that BMMSCs modified with the CXCR3 and HO-1 gene can reduce rejection of the small intestine more effectively than HO-1 modified BMMSCs and native BMMSCs.