Mesenchymal stem cell-based Smad7 gene therapy for experimental liver cirrhosis

Abstract

Background Bone mesenchymal stem cells (MSCs) can promote liver regeneration and inhibit inflammation and hepatic fibrosis. MSCs also can serve as a vehicle for gene therapy. Smad7 is an essential negative regulatory gene in the TGF-β1/Smad signalling pathway. Activation of TGF-β1/Smad signalling accelerates liver inflammation and fibrosis; we therefore hypothesized that MSCs overexpressing the Smad7 gene might be a new cell therapy approach for treating liver fibrosis via the inhibition of TGF-β1/Smad signalling. Methods MSCs were isolated from 6-week-old Wistar rats and transduced with the Smad7 gene using a lentivirus vector. Liver cirrhosis was induced by subcutaneous injection of carbon tetrachloride (CCl4) for 8 weeks. The rats with established liver cirrhosis were treated with Smad7-MSCs by direct injection of cells into the main lobes of the liver. The expression of Smad7, Smad2/3 and fibrosis biomarkers or extracellular matrix proteins and histopathological change were assessed by quantitative PCR, ELISA and Western blotting and staining. Results The mRNA and protein level of Smad7 in the recipient liver and serum were increased after treating with Smad-MSCs for 7 and 21 days (P < 0.001). The serum levels of collagen I and III and collagenase I and III were significantly (P < 0.001) reduced after the treatment with Smad7-MSCs. The mRNA levels of TGF-β1, TGFBR1, α-SMA, TIMP-1, laminin and hyaluronic acid were decreased (P < 0.001), while MMP-1 increased (P < 0.001). The liver fibrosis score and liver function were significantly alleviated after the cell therapy. Conclusions The findings suggest that the MSC therapy with Smad7-MSCs is effective in the treatment of liver fibrosis in the CCl4-induced liver cirrhosis model. Inhibition of TGF-β1 signalling pathway by enhancement of Smad-7 expression could be a feasible cell therapy approach to mitigate liver cirrhosis.

Immunomodulatory role of mesenchymal stem cell therapy in liver fibrosis

“…MSCs participate in the regulation of TGF-β downstream pathways. MSCs were able to significantly down-regulate the mRNA expression of TGF-β1 and TGFBR1 downstream molecule SMAD3 and increase the mRNA expression of SMAD7 ( 71 ). It has been demonstrated that SMAD3 upregulates the expression of the pro-fibrotic factor α-SMA or Col1a1, whereas SMAD7 has an anti-fibrotic impact.…”

Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential

“…BMSC overexpressing Smad7 significantly reduced plasma levels of laminin and hyaluronic acid, components of the ECM. Furthermore, Smad7-MSC mediated an increase in serum expression of MMP-1 and a decrease in TIMP-1 [ 131 ]. MMP is a class of matrix-degrading proteases that mainly degrade scarring in the subendothelial space.…”

Mesenchymal stromal cells: promising treatment for liver cirrhosis

“…Inflammatory cytokines induce the transdifferentiation of HSCs from a quiescent to a proliferative, migratory, and fibrotic phenotype (myofibroblast). This leads to the generation of plenty of extracellular matrix (ECM) as well as the expression of α-smooth muscle actin (α-SMA) [21]. TGF-β is the main cytokine in the stimulation of HSCs trans-differentiation and the signal of epithelial-to-mesenchymal transitions (EMT).…”