Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2024; 30(5): 471-484
Published online Feb 7, 2024. doi: 10.3748/wjg.v30.i5.471
Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model
Hui Hua, Qian-Qian Zhao, Miriam Nkesichi Kalagbor, Guo-Zhi Yu, Man Liu, Zheng-Rui Bian, Bei-Bei Zhang, Qian Yu, Yin-Hai Xu, Ren-Xian Tang, Kui-Yang Zheng, Chao Yan
Hui Hua, Qian-Qian Zhao, Miriam Nkesichi Kalagbor, Guo-Zhi Yu, Man Liu, Zheng-Rui Bian, Bei-Bei Zhang, Qian Yu, Ren-Xian Tang, Kui-Yang Zheng, Chao Yan, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, National Demonstration Center for Experimental Basic Medical Science Education, Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
Yin-Hai Xu, Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu Province, China
Co-corresponding authors: Kui-Yang Zheng and Chao Yan.
Author contributions: Hua H and Zhao QQ performed the majority of experiments; Kalagbor MN, Yu GZ, Liu M, Bian ZR, Zhang BB, Yu Q, Xu YH, and Tang RX contributed to the acquisition of data and improving the manuscript. Zheng KY and Yan C contributed equally to this work as co-corresponding authors; Zheng KY supervised the experiments, corrected the data, and revised the manuscript; Yan C conceived and designed the main content of this study and was responsible for analyzing the research results.
Supported by the National Natural Science Foundation of China, No. 82172297; Natural Science Foundation of Jiangsu Province of China, No. BK20211346 and No. BK20201011; Natural Science Foundation of Jiangsu Higher Education Institutions of China, No. 22KJA310007; and Xuzhou Science and Technology Project, No. KC22055.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Care and Use Committee of Xuzhou Medical University License (Approval No. 201801w003).
Conflict-of-interest statement: All authors declare no competing interests.
Data sharing statement: No additional data are available.
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 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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Chao Yan, MD, PhD, Academic Research, Professor, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, National Demonstration Center for Experimental Basic Medical Science Education, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou 221004, Jiangsu Province, China. yanchao6957@xzhmu.edu.cn
Received: October 7, 2023
Peer-review started: October 7, 2023
First decision: December 8, 2023
Revised: December 17, 2023
Accepted: January 12, 2024
Article in press: January 12, 2024
Published online: February 7, 2024
ARTICLE HIGHLIGHTS
Research background

Primary sclerosing cholangitis (PSC) which may progress to cholangiocarcinoma is an idiopathic cholestatic disease and there is a very limited medical option to interfere with the course of PSC. Recombinant adeno-associated virus (rAAV) provides a prospective platform for gene therapy on such kinds of diseases. A microRNA (miRNA) let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated.

Research motivation

To investigate the potential function and mechanisms of miRNA let-7a-5p transferred by rAAV8 in animal model of PSC.

Research objectives

To study the therapeutic effects of inhibition of let-7a-5p transferred by rAAV8 on a 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-induced mouse model of sclerosing cholangitis.

Research methods

A mouse model of sclerosing cholangitis was induced by 0.1% DDC feeding for 2 wk or 6 wk, and rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo onset of DDC feeding. After sacrifice of the mice, the liver and the serum were collected from each mouse. The hepatobiliary injuries, hepatic inflammation was evaluated. The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot.

Research results

The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers, and prevent the proliferation of cholangiocytes and biliary fibrosis. Furthermore, inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as SOCS1 and Dectin1, which consequently inhibition of NF-κB-mediated hepatic inflammation.

Research conclusions

Our findings suggested that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis, which provides a possible therapeutic strategy for PSC.

Research perspectives

The present study demonstrates that the rAAV-mediated miRNAs strategy may provide a promising therapeutic opportunity for this debilitating and life-threatening disease.