Human embryonic stem cell-derived mesenchymal stem cells repress liver fibrosis via enhancing of TIF1γ in mice

Abstract

Progressive liver fibrosis leads to cirrhosis and liver failure and requires liver transplantation, which is often indicated as the only effective therapy. However, the limitations of liver transplantation are associated with organ shortages and long-term immunosuppression. Recent technological advances have led to the disclosure of cellular and molecular mechanisms underlying liver fibrosis and the development of prospective therapeutic approaches to reduce or reverse liver fibrosis, which would decrease the associated morbidity and demand for liver transplantation. In this study, we performed transplantation of human embryonic stem cell-derived mesenchymal stem cells (hE-MSCs) to the livers of thioacetamide (TAA)-treated mice. The result of histological analysis using Massons trichrome staining, which detects collagen fibers, showed the recovery of TAA-induced liver fibrosis at 14 and 21 days after transplantation of hE-MSCs. To address the underlying mechanism, we screened candidate anti-fibrotic factors and selected transcriptional intermediary factor 1 (TIF1)γ. Our results indicate that TIF1γ inhibited the activation of cultured human hepatic stellate cells (HSCs), as evidenced by the decrease of smooth muscle actin (α-SMA) and collagen type I. TIF1γ was downregulated by pro-fibrotic signals such as TAA and transforming growth factor (TGF)β1 and upregulated by hE-MSCs in vivo, suggesting that TIF1γ is an anti-fibrotic factor expressed in HSCs. Using fluorescent-labeled hE-MSCs, we observed that some of the transplanted hE-MSCs survived and trans-differentiated to HSCs and could secrete paracrine hepatocyte growth factor (HGF) in TAA-treated livers. The downregulation of TIF1γ and upregulation of α-SMA shown in experimental liver fibrosis were confirmed in human cirrhotic livers. Our findings suggest that TIF1γ is a potent anti-fibrotic factor, which can be utilized in the development of novel therapeutic approaches to prevent and reverse liver fibrosis.