title: A Proinflammatory Secretome Mediates the Impaired Immunopotency of Human Mesenchymal Stromal Cells in Elderly Patients with Atherosclerosis.
abstract: Inflammation plays a pivotal role in the initiation and progression of atherosclerosis (ATH). Due to their potent immunomodulatory properties, mesenchymal stromal cells (MSCs) are evaluated as therapeutic tools in ATH and other chronic inflammatory disorders. Aging reduces MSCs immunopotency potentially limiting their therapeutic utility. The mechanisms that mediate the effect of age on MSCs immune-regulatory function remain elusive and are the focus of this study. Human adipose tissue-derived MSCs were isolated from patients undergoing coronary artery bypass graft surgery. MSCs:CD4+T-cell suppression, a readout of MSCs' immunopotency, was assessed in allogeneic coculture systems. MSCs from elderly subjects were found to exhibit a diminished capacity to suppress the proliferation of activated T cells. Soluble factors and, to a lesser extent, direct cell-cell contact mechanisms mediated the MSCs:T-cell suppression. Elderly MSCs exhibited a pro-inflammatory secretome with increased levels of interleukin-6 (IL-6), IL-8/CXCL8, and monocyte chemoattractant protein-1 (MCP-1/CCL2). Neutralization of these factors enhanced the immunomodulatory function of elderly MSCs. In summary, our data reveal that in contrast to young MSCs, MSCs from elderly individuals with ATH secrete high levels of IL-6, IL-8/CXCL8 and MCP-1/CCL2 which mediate their reduced immunopotency. Consequently, strategies aimed at targeting pro-inflammatory cytokines/chemokines produced by MSCs could enhance the efficacy of autologous cell-based therapies in the elderly. Stem Cells Translational Medicine 2017;6:1132-1140.
authors.affiliation: Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.|Division of Rheumatology, McGill University, Montreal, Quebec, Canada.
authors.forename: Özge
authors.initials: Ö
authors.lastname: Kizilay Mancini
authors.affiliation: Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.|Division of Rheumatology, McGill University, Montreal, Quebec, Canada.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Lora
authors.affiliation: Divisions of Cardiac Surgery and Surgical Research, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Shum-Tim
authors.affiliation: CRCHUM and Institut du cancer de Montréal, Montreal, Quebec, Canada.|Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Nadeau
authors.affiliation: CRCHUM and Institut du cancer de Montréal, Montreal, Quebec, Canada.|Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Rodier
authors.affiliation: Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada.|Division of Rheumatology, McGill University, Montreal, Quebec, Canada.
authors.forename: Inés
authors.initials: I
authors.lastname: Colmegna
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018920:Coculture Techniques; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D016209:Interleukin-8
keywords: Aging; Atherosclerosis; Immunopotency; Mesenchymal stromal cells