Effect of uPA gene-transfected bone marrow-derived liver stem cell transplantation on activation of hepatic stellate cells in rat liver fibrosis

Activation of hepatic stellate cells (HSCs) is a critical event in process of hepatic fibrogenesis and cirrhosis. Matrine, the active ingredient ofSophora, had been used for clinical treatment of acute/chronic liver disease. However, its potency was low. We prepared a high potency and low toxicity matrine derivate, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities on antihepatic fibrosis. This study demonstrated that WM130 results in a decreased proliferative activity of HSC-T6 cells, with the half inhibitory concentration (IC50) of 68 μM. WM130 can inhibit the migration and induce apoptosis in HSC-T6 cells at both concentrations of 68 μM (IC50) and 34 μM (half IC50). The expression ofα-SMA, Collagen I, Collagen III, and TGF-β1 could be downregulated, and the protein phosphorylation levels of EGFR, AKT, ERK, Smad, and Raf (p-EGFR, p-AKT, p-ERK, p-Smad, and p-Raf) were also decreased by WM130. On the DMN-induced rat liver fibrosis model, WM130 can effectively reduce the TGF-β1, AKT,α-SMA, and p-ERK levels, decrease the extracellular matrix (ECM) formation, and inhibit rat liver fibrosis progression. In conclusion, this study demonstrated that WM130 can significantly inhibit the activation of HSC-T6 cells and block the rat liver fibrosis progression by inducing apoptosis, suppressing the deposition of ECM, and inhibiting TGF-β/Smad and Ras/ERK pathways.

Download Full-text

Treatment Efficiency of Different Routes of Bone Marrow-Derived Mesenchymal Stem Cell Injection in Rat Liver Fibrosis Model

Cellular Physiology and Biochemistry ◽

10.1159/000492558 ◽

2018 ◽

Vol 48 (5) ◽

pp. 2161-2171 ◽

Cited By ~ 12

Author(s):

Naglaa K. Idriss ◽

Hayam G. Sayyed ◽

Amany Osama ◽

Dina Sabry

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Stem Cell ◽

Growth Factor ◽

Liver Fibrosis ◽

Mesenchymal Stem Cell ◽

Rat Liver ◽

Enzyme Linked Immunosorbent Assay ◽

Rat Liver Fibrosis ◽

Recovery Group

Background/Aims: The most appropriate route for bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation in the management of liver fibrosis remains controversial. This study investigated the therapeutic efficacy of intravenous and intrasplenic BM-MSC transplantation on carbon tetrachloride (CCl4)-induced rat liver fibrosis. Methods: Fifty rats were divided into 5 groups (n = 10 rats per group): healthy control group, CCl4 group, CCl4/ recovery group, CCl4/BM-MSC intravenous group, and CCl4/BM-MSC intrasplenic group. BM-MSCs were isolated, labeled with green fluorescent protein (GFP), and injected into fibrotic rats either intravenously or intrasplenically. Gene expression of interleukins (IL-1β and IL-6), interferon (INF)-γ, hepatic growth factor, and the hepatocyte-specific marker cytokeratin 18 was estimated by quantitative real-time reverse transcription-polymerase chain reaction. Vascular endothelial growth factor and connective tissue growth factor was detected by western blot analysis and enzyme-linked immunosorbent assay, respectively. At 2 weeks after intravenous and intrasplenic BM-MSC injections, GFP-positive cells were detected in liver tissue. Results: Both routes achieved a similar enhancement of liver function, which was confirmed by histopathological examination. The intravenous route was more effective than the intrasplenic route in reducing gene expression levels of IL-1β, IL-6, and INF-γ. However, fibrotic changes were still observed in the recovery group. Conclusion: Intravenous BM-MSC injection was an efficient and appropriate route for BM-MSC transplantation for the management of liver fibrosis.

Download Full-text