Abstract
Acute liver failure (ALF) is a serious life-threatening condition. Mesenchymal stem cells (MSCs) may be an effective treatment for this condition and a good alternative to liver transplantation. Icaritin (ICT) is an active ingredient of the genus Epimedium, a traditional Chinese medicine, with the potential to enhance the proliferation of MSCs. The purpose of this study was to explore whether ICT increased the therapeutic effects of MSCs and explore its underlying mechanisms. For in vivo experiments, a rat ALF model was established by intraperitoneal injection of D(+)-galactosamine/ lipopolysaccharide. MSCs cocultured with ICT were used to treat ALF rats and the protective effects assessed as survival rate, levels of serum AST and ALT, and histological changes in liver tissue. For in vitro experiments, MSCs were treated in serum-free culture for 72 h to simulate the disruption of intrahepatic microcirculation. MSCs apoptosis was examined to determine whether ICT rescued impaired MSCs. The role of the hepatocyte growth factor (HGF)/c-Met pathway in MSCs was assessed by constructing genetically modified MSCs overexpressing c-Met and by using the c-Met receptor inhibitor (crizotinib). The results showed that MSCs increased the survival rate of ALF rats and reduced liver damage. MSCs cocultured with ICT exerted a greater therapeutic effect than MSCs alone. Further, the HGF/c-Met pathway played a key role in the antiapoptotic activity of MSCs, which was associated with the optimized efficacy of ICT. In conclusion, this study demonstrated that ICT enhances the therapeutic effect of MSCs in a model of ALF, improving the antiapoptotic potential of MSCs by upregulation of the HGF/c-Met pathway. The combination of stem cell therapy with traditional herbal extracts may improve MSC-based clinical applications.
Highlights
Acute liver failure (ALF) is a severe, rapidly deteriorating disease characterized by the abrupt onset of severe liver injury and high mortality
MO, USA); galactosamine (D-GalN; Sigma); lipopolysaccharide (LPS; Sigma); human hepatocyte growth factor (HGF) (ReproTech, Columbia, Missouri, USA); crizotinib (MedChemExpress, Monmouth Junction, NJ, USA); monoclonal rabbit antihuman/rat antibody for cleaved caspase-3 (Cell Signaling Technology, Boston, MA, USA; no. #9664); monoclonal mouse anti-human/rat antibody for Bcl-2 (Abcam, Cambridge, MA, USA; no. ab692); monoclonal rabbit antihuman/rat antibody for Bax (Abcam; no. ab32503); monoclonal mouse anti-human/rat antibody for c-Met (ThermoFisher, Waltham, MA, USA; no. k845.5); monoclonal rabbit anti-human/rat antibodies for glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Abcam; no. ab181602); goat antirabbit IgG labeled with horseradish peroxidase (HRP; Abcam; no. ab6721) and goat anti-mice IgG labeled with HRP (Abcam; no. ab6789); and bicinchoninic acid (BCA) protein assay kit (FD, Dalian, China)
Human umbilical cord-mesenchymal stem cells (MSCs) are a type of multipotent stem cell derived from umbilical cord Wharton jelly
Summary
Acute liver failure (ALF) is a severe, rapidly deteriorating disease characterized by the abrupt onset of severe liver injury and high mortality. Liver transplantation is one of the most effective treatment for ALF; the shortage of donor organizations remains a major obstacle to its application. Mesenchymal stem cells (MSCs) have shown excellent potential for many therapeutic applications. A large number of studies based on stem cell transplantation have achieved remarkable results and provided new ways for the treatment of various diseases. For ALF, MSCs are a promising treatment because they have the potential to differentiate into hepatocytes to restore liver function and provide immune regulation to suppress inflammatory storms [1].
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