Brief Report: Proteasomal Indoleamine 2,3‐Dioxygenase Degradation Reduces the Immunosuppressive Potential of Clinical Grade‐Mesenchymal Stromal Cells Undergoing Replicative Senescence

• Published in: Stem cells (Dayton, Ohio) Vol. 35; no. 5; pp. 1431 - 1436
• Main Authors: Loisel, Séverine, Dulong, Joëlle, Ménard, Cédric, Renoud, Marie‐Laure, Meziere, Nadine, Isabelle, Bezier, Latour, Maëlle, Bescher, Nadège, Pedeux, Rémy, Bertheuil, Nicolas, Flecher, Erwan, Sensebé, Luc, Tarte, Karin
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.05.2017
• Subjects: Adipose stem cells; Adipose tissue; Bone marrow; Bone marrow stromal cells; Cell Proliferation; Cellular Senescence; Clinical translation; Degradation; Humans; Immunomodulation; Immunosuppression; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Inflammation; Lymphocytes B; Lymphocytes T; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - enzymology; Mesenchyme; Natural killer cells; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteolysis; Quality; Senescence; Stat1 protein; Stem cells; Stromal cells; T cells; T-Lymphocytes - cytology; Transcription; Tryptophan 2,3-dioxygenase; Clinical translation; Bone marrow stromal cells; Immunosuppression; T cells; Adipose stem cells; Mesenchymal stem cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2580

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 Clinical‐grade mesenchymal stromal cells produced from bone‐marrow (BM‐MSC) and adipose tissue (ADSC) inhibit T‐cell proliferation through their capacity to express functional indoleamine 2,3‐dioxygenase (IDO) in response to inflammatory stimuli, in particular IFN‐γ and TNF‐α, produced by activated T cells (A). When they enter replicative senescence (SEN+), a process associated with the production of high number of cells to treat multiple recipients from one donor, both BM‐MSC and ADSC lose their T‐cell suppressive potential, in association with a proteasome‐dependent degradation of IDO (B).