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

초록

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-beta (TGF-beta) 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, alpha-smooth muscle actin (alpha-SMA), TGF-beta 1, 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-beta 1 stimulated alpha-SMA synthesis in HSCs. DCN-MSCs exert strong protective effects against hepatic fibrosis by suppressing TGF-NSmad 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-beta (TGF-beta)/Smad signaling pathway, supported by attenuation of TGF-beta 1 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.

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