Menstrual blood‐derived mesenchymal stem cells attenuate inflammation and improve the mortality of acute liver failure combining with A2AR agonist in mice

Abstract

Background and Aim Acute liver failure (ALF) poses a serious public health issue. The menstrual blood‐derived mesenchymal stem cells (MenSCs) have been applied to cure various liver‐related diseases. However, the efficacy and mechanism are far from clear. This study aims to explore the efficacy and potential mechanism of MenSCs to cure ALF. Methods We investigate the potential mechanism of MenSCs on the ALF in vitro and in vivo. A2A adenosine receptor (A2AR) activation was investigated as the potential reinforcer for MenSCs treatment. Lipid polysaccharide/d‐galactosamine (d‐GalN) was employed to induce ALF. Diverse techniques were used to measure the inflammatory cytokines and key signaling molecules. Hematoxylin–eosin stain and aminotransaminases were applied to evaluate the liver injury. Flow cytometry was employed to assess the T cells. Results The MenSCs can decrease the lipid polysaccharide‐induced inflammatory cytokine elevation and related signaling molecules in ALF, including TLR4, phosphorylated‐NF‐kBp65 (p‐NF‐kBp65), PI3K, and p‐AKT, p‐mTOR and p‐IKK in vitro. Moreover, MenSCs also can significantly reverse the liver injury, inflammatory cytokines elevation and related signaling molecules increase, and Treg/Th17 ratio decrease in vivo. In addition, MenSCs plus A2AR agonist can enhance the above changes. Conclusions The MenSCs can attenuate the ALF‐induced liver injury via inhibition of TLR4‐mediated PI3K/Akt/mTOR/IKK signaling. Then, this inhibits the p‐NF‐κBp65 translocate into nuclear, which causes a decrease of inflammatory cytokines release. Moreover, A2AR agonist can play a synergic role with MenSCs and enhance the above‐mentioned effects.

Mesenchymal Stem Cell Therapy in Acute Liver Failure

“…Meanwhile, adenosine A2A receptor (A2AR) agonists can synergize with the menstrual blood MSCs. 72 Sang et al 73 found that MSCs transplantation combined with IL-1Ra (2 mg/kg) can significantly improve the survival time of ALF swine, which may be related to the synergistic effect of MSCs and IL-1Ra in regulating inflammation and apoptosis. In ALF rat , Human umbilical cord blood MSCs transplantation combined granulocyte colony stimulating factor can reduce liver injury by inhibiting inflammation, oxidative stress, and hepatocyte apoptosis and promoting the proliferation and colonization of MSCs.…”

Therapeutic Potential of Menstrual Blood-Derived Stem Cell Transplantation for Intrauterine Adhesions

“…In addition, in vitro studies demonstrated that MenSCs had a negative effect on macrophage bactericidal properties and the production of reactive oxygen intermediates, indicating that MenSCs effect the macrophage numbers, which provides a theoretical basis for clinical treatment in future ( 32 ). Moreover, MenSCs can have a negative effect on PI3K/Akt/mTOR/IKK signaling mediated by TLR4, leading to a decreasing of inflammatory cytokine, as p-NF-κBp65 could not be translocated into the nucleus ( 33 ). Another study showed that the maturation of human blood monocyte-derived dendritic cells was suppressed via interleukin−6 and interleukin−10(IL-10) secreted by MenSCs ( 34 ).…”

Human Menstrual Blood–Derived Endometrial Stem Cells Promote Functional Recovery by Improving the Inflammatory Microenvironment in a Mouse Spinal Cord Injury Model

“…Human menstrual blood–derived endometrial stem cells (MenSCs), an important member of the MSC family, have attracted extensive attention because of their rich sources, noninvasive collection and separation methods, high proliferative activity, and differentiation potential 22 . MenSCs have satisfactory results in the treatment of osteogenesis, cardiac, liver, lung, endometrial, stroke, and other diseases 22 – 27 . Owing to their excellent biological characteristics, MenSCs have received extensive attention as seed cells for the treatment of refractory diseases.…”