Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2020; 26(26): 3750-3766
Published online Jul 14, 2020. doi: 10.3748/wjg.v26.i26.3750
Adipose-derived mesenchymal stem cells alleviate TNBS-induced colitis in rats by influencing intestinal epithelial cell regeneration, Wnt signaling, and T cell immunity
Jian-Guo Gao, Mo-Sang Yu, Meng-Meng Zhang, Xue-Wei Gu, Yue Ren, Xin-Xin Zhou, Dong Chen, Tian-Lian Yan, You-Ming Li, Xi Jin
Jian-Guo Gao, Mo-Sang Yu, Meng-Meng Zhang, Xue-Wei Gu, Yue Ren, Xin-Xin Zhou, Tian-Lian Yan, You-Ming Li, Xi Jin, Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Dong Chen, Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Author contributions: Gao JG and Yu MS contributed equally to this work, and they designed the study and drafted the manuscript; Zhang MM, Gu XW, Ren Y, and Zhou XX performed the study; Chen D conducted the statistical analysis; Zhang MM and Yan TL provided guidance during revision; Jin X and Li YM supervised the study and provided consultation during the entire study.
Supported by National Natural Science Foundation of China, No. 81770574, No. 81600414, and No. 81600447.
Institutional animal care and use committee statement: This study was carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The animal protocol was approved by the institutional review board of the First Affiliated Hospital of Zhejiang University and adhered to the standards articulated in Animal Research. The study was reviewed and approved by Animal Experimental Ethical Inspection of the First Affiliated Hospital, College of Medicine, Zhejiang University.
Conflict-of-interest statement: The authors have no conflicts of interest to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: Authors have read the ARRIVE guidelines and prepared and revised the manuscript according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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/
Corresponding author: Xi Jin, PhD, Associate Chief Physician, Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79, Qingchun Road, Hangzhou 310003, Zhejiang Province, China. jxfl007@zju.edu.cn
Received: December 27, 2019
Peer-review started: December 27, 2019
First decision: February 14, 2020
Revised: May 14, 2020
Accepted: June 3, 2020
Article in press: June 3, 2020
Published online: July 14, 2020
Abstract
BACKGROUND

Conventional Crohn’s disease (CD) treatments are supportive rather than curative and have serious side effects. Adipose-derived mesenchymal stem cells (ADSCs) have been gradually applied to treat various diseases. The therapeutic effect and underlying mechanism of ADSCs on CD are still not clear.

AIM

To investigate the effect of ADSC administration on CD and explore the potential mechanisms.

METHODS

Wistar rats were administered with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish a rat model of CD, followed by tail injections of green fluorescent protein (GFP)-modified ADSCs. Flow cytometry, qRT-PCR, and Western blot were used to detect changes in the Wnt signaling pathway, T cell subtypes, and their related cytokines.

RESULTS

The isolated cells showed the characteristics of ADSCs, including spindle-shaped morphology, high expression of CD29, CD44, and CD90, low expression of CD34 and CD45, and osteogenic/adipogenic ability. ADSC therapy markedly reduced disease activity index and ameliorated colitis severity in the TNBS-induced rat model of CD. Furthermore, serum anti-sacchromyces cerevisiae antibody and p-anti-neutrophil cytoplasmic antibody levels were significantly reduced in ADSC-treated rats. Mechanistically, the GFP-ADSCs were colocalized with intestinal epithelial cells (IECs) in the CD rat model. GFP-ADSC delivery significantly antagonized TNBS-induced increased canonical Wnt pathway expression, decreased noncanonical Wnt signaling pathway expression, and increased apoptosis rates and protein level of cleaved caspase-3 in rats. In addition, ADSCs attenuated TNBS-induced abnormal inflammatory cytokine production, disturbed T cell subtypes, and their related markers in rats.

CONCLUSION

Successfully isolated ADSCs show therapeutic effects in CD by regulating IEC proliferation, the Wnt signaling pathway, and T cell immunity.

Keywords: Crohn’s disease, Adipose-derived mesenchymal stem cell, Intestinal epithelial cell, Wnt pathway, T cell, Inflammation

Core tip: The prevalence and mortality of Crohn’s disease (CD) have been increasing globally, including in areas of Asia that previously had a low incidence. We aimed to investigate the effect and explore potential mechanisms of adipose-derived mesenchymal stem cells (ADSCs) in a 2,4,6-trinitrobenzene sulfonic acid-induced rat model of CD. Our study for the first time provided evidence that successfully isolated ADSCs show therapeutic effects in CD by regulating intestinal epithelial cell proliferation, the Wnt signaling pathway, and T cell immunity.