In a Rat Model of Acute Liver Failure, Icaritin Improved the Therapeutic Effect of Mesenchymal Stem Cells by Activation of the Hepatocyte Growth Factor/c-Met Pathway

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.

Comparison of the effects of different mesenchymal stem cells on attenuating phosgene-induced lung injury in rats

“…In vivo, the expressions of HGF in each MSCs group differed and this was consistent with the trend of the effects of stem cells. Previous studies have reported that HGF can promote the directional migration of a variety of cells [13,14]. Moreover, HGF is closely related to the vascular endothelium function [29].…”

“…Studies have reported that HGF plays a major role in promoting migration in many tumors [11,12]. Other studies have con rmed that HGF promotes the directional migration of MSCs [13,14]. Roggia et al con rmed HGF enhanced the differentiation of embryonic stem cells [15].…”

Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review

“…A diversity of studies recently has focused on combination therapy with MSCs and other molecules or modalities to diminish ALF. Meanwhile, co-administration of MSCs with Icaritin, a well-known ingredient isolated from traditional Chinese medicine, resulted in promising outcomes in vivo [ 131 ]. Indeed, MSCs co-cultured with Icaritin improved survival, reduced serum levels of AST and ALT, and elicited histological variations in liver tissue more potently than MSCs alone.…”

“…Indeed, MSCs co-cultured with Icaritin improved survival, reduced serum levels of AST and ALT, and elicited histological variations in liver tissue more potently than MSCs alone. Importantly, the up-regulation of HGF/c-Met by Icaritin was found to be involved in MSCs-triggered antiapoptotic influences on hepatocytes, reflecting the potential of herbal extracts to promote MSC-mediated therapeutic impacts [ 131 ]. The addition of the granulocyte colony-stimulating factor (G-CSF) to UCB-MSCs also improved survival and reduced ROS and pro-inflammatory cytokines expressions in ALF murine model [ 132 ].…”

Progress of Interference of Traditional Chinese Medicine on Cirrhosis Treated with Bone Marrow Mesenchymal Stem Cells

“…Icaritin (ICT) is an active ingredient of the genus Epimedium , a traditional Chinese medicine, with the potential to enhance the proliferation of MSCs. Lu et al [ 37 ]found out that MSCs increased the survival rate of acute liver failure rats and reduced liver damage. MSCs cocultured with ICT exerted a greater therapeutic effect than MSCs alone.…”