title: Human mesenchymal stromal cells suppress T-cell proliferation independent of heme oxygenase-1.
abstract: Mesenchymal stromal cells deploy immune suppressive properties amenable for use as cell therapy for inflammatory disorders. It is now recognized that mesenchymal stromal cells necessitate priming with an inflammatory milieu, in particular interferon-γ, to exert augmented immunosuppressive effects. It has been recently suggested that the heme-catabolizing enzyme heme oxygenase-1 is an essential component of the mesenchymal stromal cell-driven immune suppressive response. Because mesenchymal stromal cells upregulate indoleamine 2,3-dioxygenase expression on interferon-γ priming and indoleamine 2,3-dioxygenase requires heme as a cofactor for optimal catabolic function, we investigated the potential antagonism of heme oxygenase-1 activity on indoleamine 2, 3-dioxygenase and the impact on mesenchymal stromal cell immune plasticity. We herein sought to evaluate the molecular genetic effect of cytokine priming on human mesenchymal stromal cell heme oxygenase-1 expression and its functional role in differentially primed mesenchymal stromal cells. Contrary to previous reports, messenger RNA and protein analyses demonstrated that mesenchymal stromal cells derived from normal subjects (n = 6) do not express heme oxygenase-1 at steady state or after interferon-γ, tumor necrosis factor-α, and/or transforming growth factor-β priming. Pharmacological inhibition of heme oxygenase-1 with the use of tin protoporphyrin did not significantly abrogate the ability of mesenchymal stromal cells to suppress T-cell proliferation in vitro. Overall, these results unequivocally demonstrate that under steady state and after cytokine priming, human mesenchymal stromal cells immunoregulate T-cell proliferation independent of heme oxygenase-1.
authors.affiliation: Departments of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Patel
authors.affiliation: Departments of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA.
authors.forename: Ian B
authors.initials: IB
authors.lastname: Copland
authors.affiliation: Departments of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Garcia
authors.affiliation: NewLink Genetics Inc, Plymouth Meeting, Pennsylvania, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Metz
authors.affiliation: Departments of Hematology & Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia, USA; Department of Pediatrics, Emory University, Atlanta, Georgia, USA. Electronic address: jgalipe@emory.edu.
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
mesh_terms: D000293:Adolescent; D000328:Adult; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D005260:Female; D006418:Heme / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007249:Inflammation / Q000628:therapy; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000201:enzymology / Q000276:immunology*; D008665:Metalloporphyrins / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008665:Metalloporphyrins; D011524:Protoporphyrins; C439524:TNF protein, human; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D006418:Heme; D007371:Interferon-gamma; C032628:tin protoporphyrin IX; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: heme oxygenase 1; immune modulation; indoleamine 2,3-dioxygenase; inflammatory cytokine priming; mechanism of T-cell suppression; mesenchymal stromal cells