title: Targeting androgen receptor in bone marrow mesenchymal stem cells leads to better transplantation therapy efficacy in liver cirrhosis.
abstract: 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.
  
  
  CONCLUSIONS
  Targeting AR, a key factor in male sexual phenotype, in BM-MSCs improves transplantation therapeutic efficacy for treating liver fibrosis.
authors.affiliation: George Whipple Lab for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Chiung-Kuei
authors.initials: CK
authors.lastname: Huang
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.forename: Kuo-Pao
authors.initials: KP
authors.lastname: Lai
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Ma
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Lin
authors.forename: Meng-Yin
authors.initials: MY
authors.lastname: Tsai
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism / Q000601:surgery*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013853:Thioacetamide / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D017472:Receptors, Interleukin-1; D013853:Thioacetamide; D002251:Carbon Tetrachloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9