Effect of Function-Enhanced Mesenchymal Stem Cells Infected With Decorin-Expressing Adenovirus on Hepatic Fibrosis

• Published in: Stem cells translational medicine Vol. 5; no. 9; pp. 1247 - 1256
• Main Authors: Jang, Yoon Ok, Cho, Mee-Yon, Yun, Chae-Ok, Baik, Soon Koo, Park, Kyu-Sang, Cha, Seung-Kuy, Chang, Sei Jin, Kim, Moon Young, Lim, Yoo Li, Kwon, Sang Ok
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2016; AlphaMed Press
• Subjects: Adenoviridae; Adenovirus; Adenoviruses; Animals; Blotting, Western; Bone marrow; Cirrhosis; Culture Media, Conditioned - pharmacology; Decorin; Decorin - metabolism; Disease Models, Animal; Fibrosis; Flow cytometry; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Humans; Immunoglobulins; Immunohistochemistry; Infections; Liver; Liver Cirrhosis; Liver regeneration; Male; Mesenchymal stem cell; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal stem cells; Mesenchymal Stromal Cells - virology; Phosphatase; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Signal Transduction - physiology; Smad3 Protein - metabolism; Stem cell transplantation; Stem cells; Thioacetamide; Tissue Engineering and Regenerative Medicine; Transforming Growth Factor beta1 - metabolism; Transforming growth factor‐β; Mesenchymal stem cell; Gene therapy; Adenovirus; Transforming growth factor-β; Liver regeneration
• ISSN: 2157-6564; 2157-6580
• DOI: 10.5966/sctm.2015-0323

: 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.