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©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
Hepatocyte nuclear factor 4α induces a tendency of differentiation and activation of rat hepatic stellate cells
Kai Liu, Ming-Gao Guo, Xiao-Li Lou, Xiao-Ya Li, Yang Xu, Wei-Dan Ji, Xuan-Dong Huang, Jia-He Yang, Ji-Cheng Duan
Kai Liu, Xiao-Ya Li, Yang Xu, Wei-Dan Ji, Jia-He Yang, Ji-Cheng Duan, Department of Molecular Oncology and Laparoscopic Surgery, Eastern Hepatobiliary Surgical Hospital and National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China
Ming-Gao Guo, Department of Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiao-Tong University, Shanghai 200233, China
Xiao-Li Lou, Department of Plastic and Reconstructive Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200438, China
Xuan-Dong Huang, Department of Oncological Surgery, Second People’s Hospital of Huai’an, Jiangsu Province 223002, China
Author contributions: Liu K, Guo MG and Lou XL performed the experiments and contributed equally to this work; Guo MG and Duan JC designed the research and contributed equally to this work; Xu Y, Ji WD, Huang XD and Yang JH contributed new reagents and analyzed data; and Liu K, Lou XL, Li XY, Guo MG and Duan JC wrote the paper.
Supported by National Natural Science Foundation of China, No. 81070359.
Ethics approval: The study was reviewed and approved by the Second Military Medical University Institutional Review Board.
Conflict-of-interest: The authors declared no competing financial interests.
Data sharing: No additional data are available.
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: Ji-Cheng Duan, MD, Department of Molecular Oncology and Laparoscopic Surgery, Eastern Hepatobiliary Surgical Hospital and National Center of Liver Cancer, Second Military Medical University, Xiang Yin Road No. 800, Shanghai 200438, China.
jichengduanren@163.com
Telephone: +86-21-81875263
Received: November 18, 2014
Peer-review started: November 19, 2014
First decision: December 26, 2014
Revised: January 15, 2015
Accepted: February 11, 2015
Article in press: February 11, 2015
Published online: May 21, 2015
Processing time: 183 Days and 4.4 Hours
AIM: To investigate the effect of hepatocyte nuclear factor 4α (HNF4α) on the differentiation and transformation of hepatic stellate cells (HSCs).
METHODS: By constructing the recombinant adenovirus vector expressing HNF4α and HNF4α shRNA vector, and manipulating HNF4α expression in HSC-T6 cells, we explored the influence of HNF4α and its induction capacity in the differentiation of rat HSCs into hepatocytes.
RESULTS: With increased expression of HNF4α mediated by AdHNF4α, the relative expression of Nanog was downregulated in HSC-T6 cells (98.33 ± 12.33 vs 41.33 ± 5.67, P < 0.001). Consequently, the expression of G-P-6 and PEPCK was upregulated (G-P-6: 14.34 ± 3.33 vs 42.53 ± 5.87, P < 0.01; PEPCK: 10.10 ± 4.67 vs 56.56 ± 5.25, P < 0.001), the expression of AFP and ALB was positive, and the expression of Nanog, Type I collagen, α-SMA, and TIMP-1 was significantly decreased. HNF4α also downregulated vimentin expression and enhanced E-cadherin expression. The ultrastructure of HNF4α-induced cells had more mitochondria and ribosomes compared with the parental cells. After silencing HNF4α expression, EPCK, E-cadherin, AFP, and ALB were downregulated and α-SMA and vimentin were upregulated.
CONCLUSION: HNF4α can induce a tendency of differentiation of HSCs into hepatocyte-like cells. These findings may provide an effective way for the treatment of liver diseases.
Core tip: Hepatocyte nuclear factor 4α (HNF4α) is an important transcription factor in liver differentiation. When enhancing HNF4α expression in hepatic stellate cell line hepatic stellate cells (HSCs)-T6, the expression of G-P-6, PEPCK, and E-cadherin was upregulated, the expression of Type I collagen, α-SMA, TIMP-1, and vimentin was downregulated, and the induced cells were positive for AFP and ALB. When silencing HNF4α expression with shRNA vector, EPCK and E-cadherin were downregulated and α-SMA and vimentin were upregulated. The results demonstrated that HNF4α can induce a tendency of differentiation of HSCs into hepatocyte-like cells. These findings may provide an effective method for treating liver diseases.
