Granulocyte-Macrophage Colony-Stimulating Factor Protects Dimethylnitrosamine-Induced Rat Liver Fibrosis By Inhibiting Transforming Growth Factor-β1 Signaling Pathway

Granulocyte-macrophage colony-stimulating factor (GM-CSF) exerts several therapeutic pharmacological effects but its role in liver fibrosis has not yet been studied. The current study investigates the inhibitory effects of GM-CSF on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. In this study, liver fibrosis was induced in Sprague-Dawley rats by intraperitoneal injections of DMN (10 mg/kg of body weight) for three consecutive days per week for four weeks. To see the inhibitory effects on disease onset, GM-CSF (50 µg/kg of body weight) was injected for 2 consecutive days per week for 4 weeks along with DMN, while to see the therapeutic effects on disease progression, the GM-CSF injection was set forth at 4 weeks after the DMN injection. We found that DMN administration produced characteristics of molecular and pathological manifestations of liver fibrosis in rats including increased expressions of collagen I, alpha-smooth muscle actin (α-SMA), and transforming growth factor beta 1 (TGF-β1), and decreased PPAR-γ expression. Similarly, elevated serum levels of aspartate aminotransferase (AST), total bilirubin level (TBIL), and decreased albumin level (ALB) were observed. Treatment with GM-CSF improved the pathological liver conditions and significantly inhibited the elevated AST and TBIL, and increased ALB serum levels to normal. GM-CSF significantly decreased collagen I, α-SMA, and TGF-β1 expression and increased peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. In conclusion, GM-CSF reduced the DMN-induced rat liver fibrosis by inhibiting TGF-β1 signaling pathway.

Human fetal skin-derived stem cell secretome reduce liver fibrosis by regulating TGF-β/Smad signal pathway

Background: Liver fibrosis resulting from chronic liver injury is one of the major causes of mortality worldwide. Stem cells-secreted secretome has been evaluated for overcoming the limitations of cell-based therapy in hepatic disease, while maintaining its advantages. Methods: In this study, we investigated the effect of human fetal skin-derived stem cells (hFFSCs) secretome in the treatment of liver fibrosis. To determine the therapeutic potential of the hFFSCs secretome in liver fibrosis, we established the CCl4-induced rat liver fibrosis model, and administered hFFSCs secretome in vivo. Moreover, we investigated the anti-fibrotic mechanism of hFFSCs secretome in hepatic stellate cells (HSCs). Results: Our results showed that hFFSCs secretom effectively reduced collagen content in liver, improved the liver function and promoted liver regeneration. In addition, we found that hFSSC secretom inhibited the TGF-β1, Smad2, Smad3, and Collagen I expression, however, increased Smad7 expression. Conclusions: In conclusions, our results suggest that hFFSCs secretome treatment could reduce CCl4-induced liver fibrosis via regulating the TGF-β/Smad signal pathway.

The Use of Antifibrotic Recombinant nAG Protein in a Rat Liver Fibrosis Model

Objectives. The “nAG” protein is the key protein mediating the regeneration of amputated limbs in salamanders. The senior author (MMA) developed the original hypothesis that since “nAG” is a “regenerative” protein, it must be also an “antifibrotic’ protein. The antifibrotic properties were later confirmed in a rabbit skin hypertrophic scar model as well as in a rat spinal cord injury model. The aim of this study is to evaluate the potential therapeutic properties of the nAG protein in a rat liver fibrosis model. Methodology. Liver fibrosis was induced using intraperitoneal injections of carbon tetrachloride (CCL4). A total of 45 rats were divided equally into 3 groups: Group I (the control group) received normal saline injections for 8 weeks, Group II received CCL4 for 8 weeks, and Group III received CCL4 and nAG for 8 weeks. At the end of the experiment, the serum levels of 6 proteins (hyaluronic acid, PDGF-AB, TIMP-1, laminin, procollagen III N-terminal peptide, and collagen IV-alpha 1 chain) were measured. Liver biopsies were also taken and the stages of live fibrosis were assessed histologically. Results. The CCL4 treatment resulted in a significant increase in the serum levels of all 6 measured proteins. The nAG treatment significantly reduced these high levels. The degree of liver fibrosis was also significantly reduced in the CCL4/nAG group compared to the CCL4 group. Conclusions. nAG treatment was able to significantly reduce the serum levels of several protein markers of liver fibrosis and also significantly reduced the histological degree of liver fibrosis.