title: Brief Report: Proteasomal Indoleamine 2,3-Dioxygenase Degradation Reduces the Immunosuppressive Potential of Clinical Grade-Mesenchymal Stromal Cells Undergoing Replicative Senescence.
abstract: Owing to their immunosuppressive properties, mesenchymal stromal cells (MSCs) obtained from bone marrow (BM-MSCs) or adipose tissue (ASCs) are considered a promising tool for cell therapy. However, important issues should be considered to ensure the reproducible production of efficient and safe clinical-grade MSCs. In particular, high expansion rate, associated with progressive senescence, was recently proposed as one of the parameters that could alter MSC functionality. In this study, we directly address the consequences of replicative senescence on BM-MSC and ASC immunomodulatory properties. We demonstrate that MSCs produced according to GMP procedures inhibit less efficiently T-cell, but not Natural Killer (NK)- and B-cell, proliferation after reaching senescence. Senescence-related loss-of-function is associated with a decreased indoleamine 2,3-dioxygenase (IDO) activity in response to inflammatory stimuli. In particular, although STAT-1-dependent IDO expression is transcriptionally induced at a similar level in senescent and nonsenescent MSCs, IDO protein is specifically degraded by the proteasome in senescent ASCs and BM-MSCs, a process that could be reversed by the MG132 proteasome inhibitor. These data encourage the use of appropriate quality controls focusing on immunosuppressive mechanisms before translating clinical-grade MSCs in the clinic. Stem Cells 2017;35:1431-1436.
authors.affiliation: SITI Laboratory, Etablissement Français du Sang, CHU Rennes, France.|UMR U917, INSERM, Université Rennes 1, Rennes, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Loisel
authors.affiliation: SITI Laboratory, Etablissement Français du Sang, CHU Rennes, France.|UMR U917, INSERM, Université Rennes 1, Rennes, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dulong
authors.affiliation: SITI Laboratory, Etablissement Français du Sang, CHU Rennes, France.|UMR U917, INSERM, Université Rennes 1, Rennes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Ménard
authors.affiliation: Etablissement Français du Sang Pyrénées Méditerranée, Université Paul Sabatier, UMR5273-INSERM U1031, Toulouse, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Renoud
authors.affiliation: UMR 1348 Pégase INRA, Saint-Gilles, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Meziere
authors.affiliation: SITI Laboratory, Etablissement Français du Sang, CHU Rennes, France.|UMR U917, INSERM, Université Rennes 1, Rennes, France.
authors.forename: Bezier
authors.initials: B
authors.lastname: Isabelle
authors.affiliation: SITI Laboratory, Etablissement Français du Sang, CHU Rennes, France.|UMR U917, INSERM, Université Rennes 1, Rennes, France.
authors.forename: Maëlle
authors.initials: M
authors.lastname: Latour
authors.affiliation: SITI Laboratory, Etablissement Français du Sang, CHU Rennes, France.|UMR U917, INSERM, Université Rennes 1, Rennes, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Bescher
authors.affiliation: UMR U917, INSERM, Université Rennes 1, Rennes, France.|UMR U1242, INSERM, Centre Eugéne Marquis, Rennes, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Pedeux
authors.affiliation: SITI Laboratory, Etablissement Français du Sang, CHU Rennes, France.|UMR U917, INSERM, Université Rennes 1, Rennes, France.|Department of Plastic, Reconstructive and Aesthetic Surgery.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bertheuil
authors.affiliation: Department of Thoracic and Cardiac Surgery, CHU Rennes, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Flecher
authors.affiliation: Etablissement Français du Sang Pyrénées Méditerranée, Université Paul Sabatier, UMR5273-INSERM U1031, Toulouse, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Sensebé
authors.affiliation: SITI Laboratory, Etablissement Français du Sang, CHU Rennes, France.|UMR U917, INSERM, Université Rennes 1, Rennes, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
mesh_terms: D049109:Cell Proliferation; D016922:Cellular Senescence; D006801:Humans; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D046988:Proteasome Endopeptidase Complex
keywords: Adipose stem cells; Bone marrow stromal cells; Clinical translation; Immunosuppression; Mesenchymal stem cells; T cells