Abstract
BackgroundAlthough it has been preclinically suggested that adipose tissue-derived mesenchymal stem cell (ADSC)-based therapy could effectively treat chronic liver diseases, the hepatic engraftment of ADSCs is still extremely low, which severely limits their long-term efficacy for chronic liver diseases. This study was designed to investigate the impact of antioxidant preconditioning on hepatic engraftment efficiency and therapeutic outcomes of ADSC transplantation in liver fibrotic mice.MethodsLiver fibrosis model was established by using intraperitoneal injection of carbon tetrachloride (CCl4) in the male C57BL/6 mice. Subsequently, the ADSCs with or without antioxidant pretreatment (including melatonin and reduced glutathione (GSH)) were administrated into fibrotic mice via tail vein injection. Afterwards, the ADSC transplantation efficiency was analyzed by ex vivo imaging, and the liver functions were assessed by biochemical analysis and histopathological examination, respectively. Additionally, a typical hydrogen peroxide (H2O2)-induced cell injury model was applied to mimic the cell oxidative injury to further investigate the protective effects of antioxidant preconditioning on cell migration, proliferation, and apoptosis of ADSCs.ResultsOur data showed that antioxidant preconditioning could enhance the therapeutic effects of ADSCs on liver function recovery by reducing the level of AST, ALT, and TBIL, as well as the content of hepatic hydroxyproline and fibrotic area in liver tissues. Particularly, we also found that antioxidant preconditioning could enhance hepatic engraftment efficiency of ADSCs in liver fibrosis model through inhibiting oxidative injury.ConclusionsAntioxidant preconditioning could effectively improve therapeutic effects of ADSC transplantation for liver fibrosis through enhancing intrahepatic engraftment efficiency by reducing oxidative injuries. These findings might provide a practical strategy for enhancing ADSC transplantation and therapeutic efficiency.
Highlights
It has been preclinically suggested that adipose tissue-derived mesenchymal stem cell (ADSC)-based therapy could effectively treat chronic liver diseases, the hepatic engraftment of Adipose tissue-derived mesenchymal stem cells (ADSCs) is still extremely low, which severely limits their long-term efficacy for chronic liver diseases
Antioxidant preconditioning could enhance tissue repair functions of ADSC transplantation for liver fibrosis To investigate the effect of antioxidant preconditioning on tissue repair functions of ADSC transplantation for liver fibrosis, the histological examination of the liver tissues was performed
Based on the helpful effects of antioxidant preconditioning on ADSC transplantation for liver fibrosis, we analyzed the hydroxyproline content in liver tissues
Summary
It has been preclinically suggested that adipose tissue-derived mesenchymal stem cell (ADSC)-based therapy could effectively treat chronic liver diseases, the hepatic engraftment of ADSCs is still extremely low, which severely limits their long-term efficacy for chronic liver diseases. ADSC transplantation has been widely used for treating liver fibrosis [2], non-alcoholic liver diseases [1, 3,4,5], and cirrhosis [6] in the preclinical studies, but the long-term therapeutic outcomes are very poor and far from satisfaction, due to the extremely low hepatic engraftment efficiency of ADSCs. In most cases, the hepatic retention of stem cells is less than 5% after cell infusion for 4 weeks [7]. It has been reported that instantaneous irradiation or vasodilators (e.g., nitroglycerin and phenytolamine) could enhance cell transplantation efficiency by increasing hepatic vascular permeability in animal models [8,9,10,11,12], these methods bring severe adverse effects including additional hepatocellular injuries and uncontrollable internal bleeding, significantly hindering their applications in real clinical practice
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