Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2018; 24(29): 3260-3272
Published online Aug 7, 2018. doi: 10.3748/wjg.v24.i29.3260
Downregulation of Hes1 expression in experimental biliary atresia and its effects on bile duct structure
Rui-Zhong Zhang, Xin-Hao Zeng, Ze-Feng Lin, Ming-Fu, Yan-Lu Tong, Vincent CH Lui, Paul KH Tam, Jonathan R Lamb, Hui-Min Xia, Yan Chen
Rui-Zhong Zhang, Xin-Hao Zeng, Ze-Feng Lin, Ming-Fu, Yan-Lu Tong, Hui-Min Xia, Yan Chen, Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
Vincent CH Lui, Paul KH Tam, Yan Chen, Department of Surgery and Pathology, University of Hong Kong, Hong Kong, China
Jonathan R Lamb, Department of Life Sciences, Faculty of Natural Sciences, Imperial College London, London SW7 2AZ, United Kingdom
Author contributions: Zhang RZ, Zeng XH and Lin ZF contributed equally to this work; Zhang RZ, Lin ZF and Fu M performed the animal work; Lin ZF and Tong YL analyzed the immunohistochemistry; Lui VC, Tam PK, Lamb JR, Xia HM and Chen Y contributed to the study design, data collection, analysis, discussion and manuscript preparation.
Supported by the Science and Technology Project of Guangzhou, No. 201707010014; and the National Natural Science Foundation of China, No. 81600399 and No. 81671498.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of Guangzhou Women and Children’s Medical Center, Guangzhou, China, No. 2015090109.
Institutional animal care and use committee statement: All animal protocols were approved by the Institutional Animal Care and Use Committee of Guangzhou Medical University, Guangzhou, China, No. 2016-007.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: In the manuscript, the ARRIVE Guidelines have been adopted.
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: Yan Chen, PhD, Honorary Research Felllow, Senior Scientist, Department of Surgery and Pathology, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China. ychenc@hku.hk
Telephone: +86-852-28199602 Fax: +86-852-28199621
Received: April 23, 2018
Peer-review started: April 23, 2018
First decision: May 9, 2018
Revised: June 3, 2018
Accepted: June 25, 2018
Article in press: June 25, 2018
Published online: August 7, 2018
ARTICLE HIGHLIGHTS
Research background

An increased number of immature biliary epithelial cells and distorted bile ductules were observed in biliary atresia (BA), but the causes of these changes are unknown. The Notch signaling pathway is related to the development and differentiation of biliary epithelial cells. The target gene Hes1 is essential for tubular formation and maintenance. However, the effect of altered Hes1 expression in biliary atresia has not been established.

Research motivation

Notch signaling is one of the main pathways involved in bile duct development. However, its function in BA is not well known. Analysis of Notch signaling molecules using an established BA animal model, and 3D cell culture system might provide novel insights into the pathogenesis of BA.

Research objectives

The expression of Notch signaling pathway-related molecules was detected in a BA mouse model. The function of Hes1 downregulation was further examined using a 3D cell culture system. The results of this study can be expanded upon in future research of human BA patients by examining Hes1 expression and its relationship with BA pathogenesis.

Research methods

Immature biliary epithelial cells and bile duct structure distortion were examined in BA patients and in a BA mouse model. The expression of Notch signaling pathway-related molecules was detected in the mouse model by qPCR, and the expression of Hes1 and its gene regulatory protein was further confirmed by Western blotting. Finally, in 3D cell culture, the effects of Hes1 inhibition induced by siRNA transfection on duct-like structure formation were observed.

Research results

The results revealed the presence of immature biliary epithelial cells and distorted structures in both the BA patients and animal model. The downregulation of Hes1 expression, together with its transcriptional co-regulator RBP-Jκ, was observed in the BA mouse model. The siRNA-mediated inhibition of Hes1 completely blocked duct-like structure formation in the 3D cell culture system. However, Hes1 expression in BA patients must be further evaluated to confirm its function in the disease process.

Research conclusions

In conclusion, the results of the current study indicate that the immature biliary epithelial cells and defective duct-like structure formation in BA might be partly related to downregulation of the expression of the Notch signaling target gene Hes1. The use of a 3D epithelial cell culture system might help to identify other potential molecules, including those involved in epithelial cell maturation and duct-like structure formation.

Research perspectives

The potential effects of Hes1 observed in the BA mouse model and cell culture involving biliary epithelial cell maturation and duct-like structure formation suggest that Hes1 might contribute to the pathogenesis of BA. However, further examination of BA patient samples is necessary to better understand the role of Hes1 in the BA disease process.