: 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.