Transcriptome profiling of IL-17A preactivated mesenchymal stem cells: a comparative study to unmodified and IFN-gamma modified mesenchymal stem cells

Published 15 February 2017Human mesenchymal stem cells pretreatment with IL-17A (MSC-17) potently enhances T cell immunosuppression but not their immunogenicity, in addition to avidly promoting the induction of suppressive regulatory T cells. The aim of this study was to identify potential mechanisms by which human MSC-17 mediate their superior immunomodulatory function. Untreated-MSC (UT-MSC), IFN-γ treated MSC (MSC-γ), and MSC-17 were assessed for their gene expression profile by microarray. Significantly regulated genes were identified for their biological functions (Database for Annotation, Visualisation and Integrated Discovery, DAVID). Microarray analyses identified 1278 differentially regulated genes between MSC-γ and UT-MSC and 67 genes between MSC-17 and UT-MSC. MSC-γ were enriched for genes involved in immune response, antigen processing and presentation, humoral response, and complement activation, consistent with increased MSC-γ immunogenicity. MSC-17 genes were associated with chemotaxis response, which may be involved in T cell recruitment for MSC-17 immunosuppression. MMP1, MMP13, and CXCL6 were highly and specifically expressed in MSC-17, which was further validated by real-time PCR. Thus, MMPs and chemokines may play a key role in mediating MSC-17 superior immunomodulatory function. MSC-17 represent a potential cellular therapy to suppress immunological T cell responses mediated by expression of an array of immunoregulatory molecules.Kisha Nandini Sivanathan, Darling Rojas-Canales, Shane T. Grey, Stan Gronthos, and Patrick T. Coate

Improving human kidney function in renovascular disease with mesenchymal stem cell therapy

CommentaryA dose escalation study of adipose-derived human mesenchymal stem cell (MSC) therapy was studied in 21 subjects. This dose escalation study confirmed no significant cellular toxicity, but it showed improvement in renal oxygenation and glomerular filtration rate. No significant renal toxicity from cell therapy was shown. A reduction in inflammatory markers including tumor necrosis factor-a, interferon-g, and neutrophil gelatinase-associated lipocalin was noted in subjects receiving MSC therapy. This study provides short-term safety and renal efficacy for MSC therapy and paves the way forward for future MSC-based interventions in renovascular disease.Kisha N. Sivanathan, and P. Toby Coate

Enteric nervous system-derived IL-18 orchestrates mucosal barrier immunity

Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.Abigail Jarret, Ruaidhrí Jackson, Coco Duizer, Marc E.Healy Jun Zhao, Joseph M.Rone ... et al