title: Effect of Function-Enhanced Mesenchymal Stem Cells Infected With Decorin-Expressing Adenovirus on Hepatic Fibrosis.
abstract: : Bone marrow-derived mesenchymal stem cells (BM-MSCs) are known to have an antifibrotic effect and could be used as vehicles for targeted gene delivery. Decorin plays a protective role against fibrogenesis by modulating the degradation of the extracellular matrix. The aim of this study was to determine whether the antifibrotic effect of a combination treatment consisting of BM-MSCs and decorin on hepatic fibrosis is superior to BM-MSCs alone. The effects of BM-MSCs infected with decorin-expressing adenovirus (DCN-MSCs) on hepatic fibrosis were examined in a rat model of thioacetamide (TAA)-induced cirrhosis. The effects of infection with decorin-expressing adenovirus and of incubation with the conditioned medium of DCN-MSCs on transforming growth factor-β (TGF-β) signaling were analyzed in immortalized human hepatic stellate cells (HSCs). According to the Laennec fibrosis scoring system, cirrhotic livers from rats treated with DCN-MSCs exhibited histological improvement compared with cirrhotic livers from rats treated with control adenovirus-infected MSCs (CA-MSCs). DCN-MSC treatment reduced hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA-induced cirrhosis. These protective effects were more potent with DCN-MSCs than with CA-MSCs. The upregulation of collagen-1, α-smooth muscle actin (α-SMA), TGF-β1, and Smad3 phosphorylation in cirrhotic livers was prevented by DCN-MSC administration. Intriguingly, medium from cultured DCN-MSCs blocked both Smad3 phosphorylation and exogenous TGF-β1 stimulated α-SMA synthesis in HSCs. DCN-MSCs exert strong protective effects against hepatic fibrosis by suppressing TGF-β/Smad signaling. Thus, treatment with DCN-MSCs is a potentially novel and efficient therapeutic approach for patients with intractable cirrhosis.
  
  
  
  A combination treatment consisting of bone marrow-derived mesenchymal stem cells (BM-MSCs) and decorin strongly inhibited the progression of thioacetamide-induced hepatic fibrosis in rats, compared with BM-MSCs alone. Furthermore, the significant inhibitory effect of BM-MSCs infected with decorin-expressing adenovirus was attributed to suppressing transforming growth factor-β (TGF-β)/Smad signaling pathway, supported by attenuation of TGF-β1 expression and inhibition of Smad3 phosphorylation. Therefore, treatment with BM-MSCs infected with decorin-expressing adenovirus could constitute a novel and efficient therapeutic approach for patients with intractable cirrhosis.
authors.affiliation: Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
authors.forename: Yoon Ok
authors.initials: YO
authors.lastname: Jang
authors.affiliation: Department of Pathology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
authors.forename: Mee-Yon
authors.initials: MY
authors.lastname: Cho
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
authors.affiliation: Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea baiksk@yonsei.ac.kr.
authors.forename: Soon Koo
authors.initials: SK
authors.lastname: Baik
authors.affiliation: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
authors.forename: Kyu-Sang
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
authors.forename: Seung-Kuy
authors.initials: SK
authors.lastname: Cha
authors.affiliation: Department of Preventive Medicine and Institute of Occupational Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
authors.forename: Sei Jin
authors.initials: SJ
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
authors.forename: Moon Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
authors.forename: Yoo Li
authors.initials: YL
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.
authors.forename: Sang Ok
authors.initials: SO
authors.lastname: Kwon
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D017077:Culture Media, Conditioned / Q000494:pharmacology; D058575:Decorin / Q000378:metabolism*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000821:virology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D058575:Decorin; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1
keywords: Adenovirus; Gene therapy; Liver regeneration; Mesenchymal stem cell; Transforming growth factor-β