Mesenchymal stem cells attenuate sepsis-induced liver injury via inhibiting M1 polarization of Kupffer cells

Abstract

Sepsis is a leading cause of death in intensive care units that can result in acute hepatic damage. Animal experiments and clinical trials have shown that mesenchymal stem cell (MSC) therapy has some beneficial in several liver diseases. However, the protective effects of MSC therapy on sepsis-induced hepatic damage and associated mechanisms are not completely understood. The aim of the present study was to investigate the effects of MSCs on sepsis-induced liver injury and underlying mechanisms. A rat model of sepsis-induced liver injury was established by cecal ligation and puncture, and serum alanine aminotransferase and aspartate transaminase activities as well as liver histological changes were measured. Inflammatory cytokines, Kupffer cell M1 phenotype markers, and associated signal molecules were also determined in septic rats and in lipopolysaccharide (LPS)-treated Kupffer cells. Our results showed that injection of MSCs attenuated sepsis-induced liver injury. Treatment with MSCs inhibited activation of Kupffer cells towards M1 phenotype, attenuated TNF-α and IL-6 expression, and promoted IL-4 and IL-10 expression in septic rats and LPS-treated Kupffer cells. Furthermore, MSCs also inhibited the nuclear translocation of nuclear factor-kappa B in LPS-challenged Kupffer cells and the liver of septic rats. These results indicated that MSCs attenuated sepsis-induced liver injury through suppressing M1 polarization of Kupffer cells.

Efficacy of mesenchymal stem cell therapy for sepsis: A meta-analysis of preclinical studies

“…A previous meta-analysis [42] collected and evaluated preclinical evidence regarding the use of MSCs in animal models of sepsis and demonstrated that MSC therapy could reduce the odds of death. The updated meta-analysis presented here includes another seven high-quality studies [27,[29][30][31][32][33]41] that were mainly published in recent 3 years, and confirms the potential therapeutic efficacy of MSCs for reducing the mortality rate of sepsis in animal models, thus, providing possibilities for MSC therapy in preclinical studies of sepsis. To our knowledge, two small clinical phase 1 trials [43,44] have been performed to evaluate the safety and feasibility of MSC therapy in sepsis and septic shock patients.…”

“…Liang et al [41] proved that adipose-derived mesenchymal stem cells (ADMSCs) can reduce liver damage and inflammation through soluble tumor necrosis factor receptor 1 (sTNFR1), and more importantly, ADMSCs can significantly improve the survival rate of rats with CLP-induced sepsis. Two studies [33,49] suggest that the expression levels of various pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, are elevated in CLP rats or LPS-treated Kupffer cells. Moreover, these studies found that MSCs have inhibitory effects on the sepsis-induced overexpression of TNF-α and IL-6 and enhancing effects on IL-4 and IL-10 expression in rats with sepsis and LPS-treated Kupffer cells.…”

Efficacy of mesenchymal stem cell therapy for sepsis: A meta-analysis of preclinical studies

“…A previous meta-analysis [38] collected and evaluated preclinical evidence regarding the use of MSCs in animal models of sepsis and demonstrated that MSC therapy could reduce the odds of death. The updated meta-analysis presented here includes another seven high-quality studies [27,36,37,[39][40][41][42] that were mainly published in the last three years, and confirms the potential therapeutic efficacy of MSCs for reducing the mortality rate of sepsis in animal models, thus, providing possibilities for MSC therapy in preclinical studies of sepsis. To our knowledge, two small clinical phase 1 trials [43,44] have been performed to evaluate the safety and feasibility of MSC therapy in sepsis and septic shock patients.…”

“…Liang et al [41] proved that adipose-derived mesenchymal stem cells (ADMSCs) can reduce liver damage and inflammation through soluble tumor necrosis factor receptor 1 (sTNFR1), and more importantly, ADMSCs can significantly improve the survival rate of rats with CLP-induced sepsis. Two studies [42,49] suggest that the expression levels of various proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, are elevated in CLP rats or LPS-treated Kupffer cells. Moreover, these studies found that MSCs have inhibitory effects on the sepsis-induced overexpression of TNF-α and IL-6 and enhancing effects on IL-4 and IL-10 expression in rats with sepsis and LPS-treated Kupffer cells.…”

“…Firstly, our study provides an upto-date meta-analysis of the effectiveness of MSCs in sepsis animal models. Although a previously published meta-analysis [38] assessed the effectiveness of MSCs in sepsis animal models, the meta-analysis presented here includes seven recently published high-quality studies [27,36,37,[39][40][41][42].…”