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. Significance 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.

Keywords

• Mesenchymal stem cell
• Adenovirus
• Gene therapy
• Liver regeneration
• Transforming growth factor‐β