Abstract
Background:Endotoxemia is related to worse clinical outcomes in acute liver failure (ALF), but its management remains unsatisfactory. In this study, we aimed to assess whether the application of bone marrow mesenchymal stem cells (BMSCs) could eliminate endotoxemia and protect rats against ALF induced by thioacetamide (TAA).Methods:BMSCs were isolated from rats and identified by the specific morphology, differentiation potential, and surface markers. The optimal dose of TAA for this study was explored and TAA-induced ALF rats were randomized to three groups: the normal control group (Saline), ALF group (TAA + Saline), and BMSCs-treated group (TAA + BMSCs). The intestinal migration and differentiation of BMSCs was tracked in vivo, and intestinal permeability, endotoxin and inflammatory cytokines, histology, and mortality were analyzed. Moreover, we added the inhibitor of the PI3K/AKT/mTOR signaling pathway into the co-culture system of BMSCs with enterocytes and then performed CK and Villin expression experiments to assess the role of PI3K/AKT/mTOR signal pathway in the intestinal differentiation of BMSCs.Results:BMSCs migrated to the intestinal injury sites and differentiated into enterocytes, intestinal permeability was decreased compared with the ALF group. The higher expression of endotoxin and inflammatory cytokines were reversed after BMSCs transplantation in rats with ALF. Mortality and intestinal lesion were significantly decreased. Blocking the PI3K/AKT/mTOR signal pathway inhibited BMSCs’ intestinal differentiation in vitro.Conclusion:BMSCs can eliminate endotoxemia and reduce mortality in rats with ALF, and the PI3K/AKT/mTOR signal pathway is involved in intestinal differentiation. BMSCs transplantation could be a potential candidate for the treatment of endotoxemia in ALF.
Highlights
Acute liver failure (ALF) is characterized by a sudden development of liver dysfunction and rapid hepatocellular necrosis, may progress to hepatic coma even death due to various etiologies, including drug toxicity, hepatic ischemia, immune-mediated attack, and viral hepatitis such as hepatitis B and hepatitis C [1, 2]
We added the inhibitor of the PI3K/AKT/ mammalian target of rapamycin (mTOR) signaling pathway into the co-culture system of bone marrow mesenchymal stem cells (BMSCs) with enterocytes and performed CK and Villin expression experiments to assess the role of PI3K/AKT/mTOR signal pathway in the intestinal differentiation of BMSCs
About 72–96 h after injection of the BrdU-labeled BMSCs, the results showed the transplanted BMSCs had migrated into the injured intestine and differentiated into enterocytes (BrdU?Villin? cells) (Fig. 3B)
Summary
Acute liver failure (ALF) is characterized by a sudden development of liver dysfunction and rapid hepatocellular necrosis, may progress to hepatic coma even death due to various etiologies, including drug toxicity, hepatic ischemia, immune-mediated attack, and viral hepatitis such as hepatitis B and hepatitis C [1, 2]. It has been reported that histamine was toxic for HT29 intestinal cells and induced cell apoptosis in a comparative analysis [9] These data strongly suggest that liver function is essential to maintain a healthy intestinal environment. The gut barrier damage could promote intestinal bacteria-endotoxin translocation and endotoxemia, which can increase the severity of the liver disease. It is a vicious circle between liver and gut, the high mortality will be the last result. We aimed to assess whether the application of bone marrow mesenchymal stem cells (BMSCs) could eliminate endotoxemia and protect rats against ALF induced by thioacetamide (TAA). CONCLUSION: BMSCs can eliminate endotoxemia and reduce mortality in rats with ALF, and the PI3K/AKT/mTOR signal pathway is involved in intestinal differentiation. BMSCs transplantation could be a potential candidate for the treatment of endotoxemia in ALF
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