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
Abstract
BACKGROUND

Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options. Recombinant adeno-associated virus (rAAV) provides a promising 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.

AIM

To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8 (rAAV8) on a xenobiotic-induced mouse model of sclerosing cholangitis.

METHODS

A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) feeding for 2 wk or 6 wk. A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding. Upon sacrifice, the liver and the serum were collected from each mouse. The hepatobiliary injuries, hepatic inflammation and fibrosis were evaluated. The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot.

RESULTS

rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk. 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 suppressor of cytokine signaling 1 and Dectin1, which consequently inhibit of NF-κB-mediated hepatic inflammation.

CONCLUSION

Our study demonstrates 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 clinical translation of PSC of human.

Keywords: Primary sclerosing cholangitis, Recombinant adeno-associated virus 8, Let-7a-5p, Therapeutic effects, Inflammation

Core Tip: Primary sclerosing cholangitis (PSC) have a high risk of cholangiocarcinoma with a lack of effective treatment options. Then the present study aimed to investigate the therapeutic effects of inhibition of a microRNA let-7a transferred by recombinant adeno-associated virus 8 (rAAV8) on a 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine-induced mouse model of sclerosing cholangitis. And the results of our study demonstrates 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 clinical human clinical translation of PSC.