SDF-1/CXCR4 Augments the Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells in the Treatment of Lipopolysaccharide-Induced Liver Injury by Promoting Their Migration Through PI3K/Akt Signaling Pathway

Abstract

Mesenchymal stem cells (MSCs) are thought to have great potential in the therapy of acute liver injury. It is possible that these cells may be regulated by the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling axis, which has been shown to promote stem cells migration in the inflammation-associated diseases. However, the effects of SDF-1/CXCR4 axis on the MSCs-transplantation-based treatment for acute liver injury and the underlying mechanisms are largely unknown. In this study, we sought to determine whether SDF-1/CXCR4 would augment the therapeutic effect of bone marrow mesenchymal stem cells (BMSCs) by promoting their migration, which may result from activating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, in a rat acute liver injury model induced by lipopolysaccharide (LPS). We found that BMSCs transplantation markedly attenuated liver injury and improved the survival of LPS-treated rats. Of interest, overexpression of CXCR4 in BMSCs could substantially promote their migration both in vitro and in vivo, and result in even better therapeutic effects. This might be attributed to the activation of PI3K/Akt signaling pathway in BMSCs that is downstream of CXCR4, as demonstrated by the use of the CXCR4 antagonist AMD3100 and PI3K pathway inhibitor LY294002 assays in vitro and in vivo. Together, our results unraveled a novel molecular mechanism for the therapeutic effect of BMSCs for the treatment of acute liver injury, which may shed a new light on the clinical application of BMSCs for acute liver failure.

Efficacy of Oxymatrine Plus Antiviral in the Treatment of Sepsis and Its Effect on the Levels of Endotoxin and Inflammatory Factors

“…Endotoxin, an important pathogenic factor causing sepsis, stimulates monocytes to produce a variety of proinflammatory factors, thus releasing inflammatory factors through a series of phosphorylation pathways. These inflammatory factors further prompt the release of inflammatory mediators and the generation of hydrolase and oxygen-free radicals, leading to typical symptoms of sepsis such as pathological coagulation, vasodilation, and organ dysfunction [ 18 – 21 ]. All these results indicated that oxymatrine plus antiviral therapy could effectively reduce the levels of endotoxin and inflammatory reactions in patients and protect organ function.…”

SDF-1/CXCR4 axis promotes osteogenic differentiation of BMSCs through the JAK2/STAT3 pathway

“…In conclusion, our results suggest that SDF-1/ /CXCR4 activates JAK2/STAT3 to regulate the osteogenic differentiation of BMSCs; however, there are still some shortcomings in this study. Xiu et al [31] confirmed that SDF-1/CXCR4 can promote the migration of BMSCs and enhance SDF-1/CXCR4 therapeutic effect of BMSCs in LPS-induced acute liver injury, which is caused by the activation of the PI3K/ /Akt signaling pathway. Therefore, it is important to study the effect of SDF-1/CXCR4 on other aspects of BMSCs function, including their migration.…”

Emerging Importance of Chemokine Receptor CXCR4 and Its Ligand in Liver Disease

“…Currently, mesenchymal stem cells (MSCs) from different sources are considered to have enormous potential in the treatment of acute liver injury ( Deng et al, 2014 ; Xiu et al, 2020 ). These cells need to migrate to the injury sites to function, which may be regulated by the CXCL12/CXCR4 signaling axis.…”

“…Interestingly, overexpression of CXCR4 in BMSCs can substantially promote their migration and result in even better therapeutic effects for acute liver injury. This may be attributed to the activation of PI3K/Akt signaling pathway in BMSCs that is downstream of CXCR4 ( Xiu et al, 2020 ). The CXCL12/CXCR4 axis similarly regulates the migration of umbilical cord-derived mesenchymal stem cells (UC-MSCs) to the injured liver.…”