Contributors: Etablissement français du sang Rennes (EFS Bretagne); Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC); Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ); Etablissement français du sang Pyrénées-Méditerranée (EFS Pyrénées-Méditerranée); Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage Rennes (PEGASE); Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST; Chemistry, Oncogenesis, Stress and Signaling (COSS); Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC); UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM); Service de chirurgie plastique, reconstructive et esthétique Rennes = Cosmetic Reconstructive and Plastic surgery Rennes; Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Ponchaillou; Service de chirurgie thoracique cardiaque et vasculaire Rennes = Thoracic and Cardiovascular Surgery Rennes; Funded by Agence Nationale de la Recherche. Grant Number: ANR-11-RPIB-0012; Etablissement Français du Sang. Grant Number: APR 2016; Infrastructure program EcellFRANCE. Grant Number: ANR-11-INSB-005; European Center for Transplantation Sciences and Immunotherapy. Grant Number: IHU CESTI, ANR-10-IBHU_0005; ANR-11-RPIB-0012,SAFE,Production sécurisée de Cellules stromales du tissu adipeux pour la thérapie cellulaire(2011)
Abstract: International audience ; 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.
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