Mesenchymal stem cells alleviate bacteria‐induced liver injury in mice by inducing regulatory dendritic cells

Abstract

Fulminant hepatic failure (FHF) is a clinical syndrome characterized by sudden and severe impairment of liver function. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for FHF. In this study we used Propionibacterium acnes (P. acnes)-primed, lipopolysaccharide (LPS)-induced liver injury in mice as an animal model of human FHF. We demonstrated that administration of MSCs significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS-induced FHF. Allogeneic MSCs showed similar treatment efficacy as autologous MSCs did in FHF. Treatment efficacy of MSCs could be attributed to decreased infiltration and activation of CD4+ T cells in the liver, inhibition of T helper 1 cells, and induction of regulatory T cells (Tregs). Moreover, decreased DNA copies of P. acnes were detected in the liver of MSC-treated mice. Intriguingly, a distinct liver population of CD11c+MHCIIhiCD80loCD86lo regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor-β production. Further mechanistic studies demonstrated that MSC-derived prostaglandin E2 and one of its receptors, EP4, played essential roles in the differentiation of CD11c+B220− DC precursors into regulatory DCs in a phosphoinositide 3-kinase-dependent manner. Conclusion: MSCs induce regulatory DCs from CD11c+B220− DC precursors. This study elucidates an immunoregulatory mechanism of MSCs and lays a foundation for application of MSCs in FHF therapy. (Hepatology 2014;59:671–682)

Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase3 pathway regulation

“…Among numerous soluble factors, PGE2 is the most well-characterized, affecting Th17 differentiation and regulating modulatory macrophages and dendritic cells [66, 67]. In vitro data revealed the important role of PGE2 in suppressing Kupffer cell apoptosis.…”

Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives

“…Thus, therapeutic avenues/strategies able to protect hepatocytes/biliary duct cells from insults and/ or to modulate inflammation could prevent the development of liver fibrosis/cirrhosis. It is worth noting that MSCs are immune-privileged cells able to inhibit or modulate immune responses through different and complex mechanisms, some of them causing a reduction in the amplification of proinflammatory signals [52][53][54][55], which were the subject of recent and detailed reviews [51,[56][57][58] and are briefly summarized in Fig. 2.…”

Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

“…As in previous cellular contexts, diverse molecular contributions are thought to mediate MSC-modulation of DCs. For example, IL-6 has been shown to at least partially contribute to MSC-mediated inhibition of DC differentiation from bone marrow progenitors [43] , and PGE2 from MSCs has been shown to convert mature CD11c + B220 -DCs into a regulatory subset [44] .…”