Targeting androgen receptor in bone marrow mesenchymal stem cells leads to better transplantation therapy efficacy in liver cirrhosis.

Abstract

UNLABELLED:

Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat liver cirrhosis, an irreversible disease that may eventually lead to liver cancer development. However, low survival rate of the BM-MSCs leading to unsatisfactory efficacy remains a major concern. Gender differences have been suggested in BM-MSCs therapeutic application, but the effect of the androgen receptor (AR), a key factor in male sexual phenotype, in this application is not clear. Using two liver cirrhosis mouse models induced by CCl4 or thioacetamide, we showed that targeting AR in the BM-MSCs improved their self-renewal and migration potentials and increased paracrine effects to exert anti-inflammatory and anti-fibrotic actions to enhance liver repair. Mechanism dissection studies suggested that knocking out AR in BM-MSCs led to improved self-renewal and migration by alteration of the signaling of epidermal growth factor receptor and matrix metalloproteinase 9 and resulted in suppression of infiltrating macrophages and hepatic stellate cell activation through modulation of interleukin (IL)1R/IL1Ra signaling. Therapeutic approaches using either AR/small interfering RNA or the AR degradation enhancer, ASC-J9, to target AR in BM-MSCs all led to increased efficacy for liver repair.

CONCLUSION:

Targeting AR, a key factor in male sexual phenotype, in BM-MSCs improves transplantation therapeutic efficacy for treating liver fibrosis.

• Authors: Chiung-Kuei Huang, Soo Ok Lee, Kuo-Pao Lai, Wen-Lung Ma, Tzu-Hua Lin, Meng-Yin Tsai, Jie Luo, Chawnshang Chang
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 57 Issue 4 Pg. 1550-63 (Apr 2013) ISSN: 1527-3350 [Electronic] United States
• PMID: 23150236 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• RNA, Small Interfering
• Receptors, Androgen
• Receptors, Interleukin-1
• Thioacetamide
• Carbon Tetrachloride
• EGFR protein, mouse
• ErbB Receptors
• Matrix Metalloproteinase 9

Topics

• Animals
• Carbon Tetrachloride (adverse effects)
• Disease Models, Animal
• ErbB Receptors (metabolism)
• Female
• Liver Cirrhosis (chemically induced, metabolism, surgery)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mesenchymal Stem Cell Transplantation
• Mice
• Mice, Knockout
• Phenotype
• RNA, Small Interfering (pharmacology)
• Receptors, Androgen (drug effects, genetics)
• Receptors, Interleukin-1 (metabolism)
• Signal Transduction (physiology)
• Thioacetamide (adverse effects)
• Treatment Outcome