4 years ago

Mitochondrial Oxidative Stress Reduces the Immunopotency of Mesenchymal Stromal Cells in Adults with Coronary Artery Disease.

Yan Burelle, Ines Colmegna, Dominique Shum-Tim, Alexanne Cuillerier, Maximilien Lora, Ursula Stochaj, Ozge Kizilay Mancini, Reggie C Hamdy, Marc J Servant
Rationale: Mesenchymal stromal cells (MSCs) are promising therapeutic strategies for coronary artery disease (CAD), however, donor-related variability in cell quality is a main cause of discrepancies in preclinical studies. In vitro, MSCs from individuals with CAD have reduced ability to suppress activated T-cells. The mechanisms underlying the altered immunomodulatory capacity of MSCs in the context of atherosclerosis (ATH) remain elusive. Objective: The aim of this study was to assess the role of mitochondrial dysfunction in the impaired immunomodulatory properties of MSCs from ATH patients. Methods and Results: Adipose tissue-derived MSCs were isolated from ATH (n=38) and Non ATH (n=42) donors. MSCs:CD4(+) T-cell suppression, was assessed in allogeneic co-culture systems. Compared to Non ATH-, ATH-MSCs displayed higher levels of both intracellular (p=0.006) and mitochondrial (p=0.03) reactive oxygen species (ROS) reflecting altered mitochondrial function. The increased mitochondrial ROS levels of ATH-MSCs promoted a phenotypic switch characterized by enhanced glycolysis and an altered cytokine secretion (interleukin-6 (IL-6) p<0.0001, IL-8/CXCL8 p=0.04, and monocyte chemoattractant protein-1 (MCP-1/CCL2) p=0.01). Furthermore, treatment of ATH-MSCs with the ROS scavenger N-acetyl-L-cysteine (NAC) reduced the levels of IL-6, IL-8/CXCL8, and MCP-1/CCL2 in the MSC secretome and improved MSCs immunosuppressive capacity (p=0.03). Conclusions: An impaired mitochondrial function of ATH-MSCs underlies their altered secretome, and reduced immunopotency. Interventions aimed at restoring the mitochondrial function of ATH-MSCs improve their in vitro immunosuppressive ability, and may translate into enhanced therapeutic efficiency.

Publisher URL: http://doi.org/10.1161/CIRCRESAHA.117.311400

DOI: 10.1161/CIRCRESAHA.117.311400

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