Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 21, 2019; 25(7): 824-836
Published online Feb 21, 2019. doi: 10.3748/wjg.v25.i7.824
Ubiquitin-specific protease 22 enhances intestinal cell proliferation and tissue regeneration after intestinal ischemia reperfusion injury
An-Long Ji, Tong Li, Guo Zu, Dong-Cheng Feng, Yang Li, Guang-Zhi Wang, Ji-Hong Yao, Xiao-Feng Tian
An-Long Ji, Tong Li, Guo Zu, Dong-Cheng Feng, Yang Li, Guang-Zhi Wang, Xiao-Feng Tian, Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
Ji-Hong Yao, Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning Province, China
Author contributions: Ji AL and Li T contributed equally to the present study; Ji AL, Zu G, Li T, Feng DC, Li Y, and Wang GZ performed the experiments and analysed the data; Li T and Ji AL wrote the article; Yao JH and Tian XF designed the experiments, revised the article, and obtained research funding; all authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81679154.
Institutional review board statement: The study was reviewed and approved by the Dalian 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 Dalian Medical University.
Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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/
Corresponding author: Xiao-Feng Tian, MD, PhD, Director, Professor, Surgeon, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou District, Dalian 116023, Liaoning Province, China. txfdl@dmu.edu.cn
Telephone: +86-411-86110010 Fax: +86-411-86110010
Received: November 6, 2018
Peer-review started: November 12, 2018
First decision: November 29, 2018
Revised: January 10, 2019
Accepted: January 18, 2019
Article in press: January 18, 2019
Published online: February 21, 2019
ARTICLE HIGHLIGHTS
Research background

Ubiquitin-specific protease 22 (USP22) is a novel member of the USPs subfamily, acting as a regulator of cell cycle progression, proliferation, and tumor invasion. Decreased expression of USP22 has been identified to contribute to arrested cell cycle and disrupted generation of differentiated cell types in crypts and villi. However, the regulatory mechanism of USP22 remains unclear. Therefore, elucidation of the underlying mechanism may help to improve the tissue repair in intestinal ischemia reperfusion (I/R) injury.

Research motivation

It is necessary to explore whether USP22 is correlated with increased potential of cell proliferation and tissue regeneration in intestinal I/R injury. Recent studies have demonstrated that insufficient proliferation and regeneration of fully rescuing intestinal mucosal barrier function could be witnessed by the high mortality rate in clinical practice. Moreover, the potential role of USP22 in cell growth, cell cycle progression, and generation of differentiated cell types has also been reported in crypts and villi. These findings give us a good lead for further study regarding the mechanism of USP22 regulation during intestinal I/R injury.

Research objectives

In the previous study, we investigated the effect of USP22 on intestinal cell proliferation and regeneration after intestinal I/R injury both in vivo and in vitro by gain- and loss-of-function approaches. Our study provides significant insight into the signalling mechanism of USP22 during intestinal I/R injury that may contribute to the future investigation of more effective therapies in clinical practice.

Research methods

Experiments using an animal model and in vitro model in rats and cells to better elucidate the pathophysiological process of intestinal I/R injury. Hematoxylin and eosin staining and Chiu’s scoring system were used to demonstrate the intestinal tissue injury histopathologically. Immunohistochemical staining for PCNA was carried out to display and observe positive nuclei of proliferating intestinal cells. Gene silencing or transfection was conducted to construct relatively stable USP22-depleted or -expressed cells to complete the following functional studies. A series of in vitro experiments, such as Western blot, Cell Counting Kit-8, and cell cycle analysis, were performed to explore the effect of USP22 on cell proliferation.

Research results

Experiments in vivo showed the correlation between USP22 and intestinal regenerative activity of intestinal cells after intestinal I/R injury. The results of in vitro experiments showed a direct positive correlation of USP22 with cell proliferation and cell cycle progression of intestinal cells after hypoxia/reoxygenation injury. This study could be valuable for consultation in further study on intestinal I/R injury and be potentially utilized in therapeutic enhancement in clinical practice. Limitations did exist that the in vivo study should be better designed to imply causation and biological linkage and USP22 knockout mouse models would be helpful. Clinical samples are also needed to better suit the application on human beings.

Research conclusions

USP22 plays a positive role in intestinal epithelial cell proliferation and tissue regeneration in intestinal I/R injury. This study reveals a novel role for USP22 in intestinal regeneration after I/R injury. Targeting USP22 may increase the therapeutic potential for intestinal I/R injury in clinical practice.

Research perspectives

Our study illuminates the role of USP22 in intestinal epithelial cell proliferation and tissue regeneration in intestinal I/R injury. Other researchers have reported the abundant mucus secreting goblet cells in a USP22 globally reduced mouse model. While goblet cells are also one of indispensable parts in regulating innate immune function, further investigation is needed.