Ozge Kizilay Mancini1, Maximilien Lora1, Alexanne Cuillerier1, Dominique Shum-Tim1, Reggie Hamdy1, Yan Burelle1, Marc J Servant1, Ursula Stochaj1, Inés Colmegna2. 1. From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada. 2. From the Department of Anatomy and Cell Biology (O.K.M.), Department of Physiology (U.S.), Divisions of Cardiac Surgery and Surgical Research, Department of Surgery (D.S.T.), Division of Rheumatology, Department of Medicine (I.C., M.L.) McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children (R.H.); Department of Cellular and Molecular Medicine, Faculty of Medicine (A.C., Y.B.), University of Ottawa, Ontario, Canada; and Faculty of Pharmacy (M.J.S.), University of Montreal, Quebec, Canada. ines.colmegna@mcgill.ca.
Abstract
RATIONALE: Mesenchymal stromal cells (MSCs) are promising therapeutic strategies for coronary artery disease; however, donor-related variability in cell quality is a main cause of discrepancies in preclinical studies. In vitro, MSCs from individuals with coronary artery disease have reduced ability to suppress activated T-cells. The mechanisms underlying the altered immunomodulatory capacity of MSCs in the context of atherosclerosis remain elusive. OBJECTIVE: The aim of this study was to assess the role of mitochondrial dysfunction in the impaired immunomodulatory properties of MSCs from patients with atherosclerosis. METHODS AND RESULTS: Adipose tissue-derived MSCs were isolated from atherosclerotic (n=38) and nonatherosclerotic (n=42) donors. MSCs:CD4+T-cell suppression was assessed in allogeneic coculture systems. Compared with nonatherosclerotic-MSCs, atherosclerotic-MSCs displayed higher levels of both intracellular (P=0.006) and mitochondrial (P=0.03) reactive oxygen species reflecting altered mitochondrial function. The increased mitochondrial reactive oxygen species levels of atherosclerotic-MSCs promoted a phenotypic switch characterized by enhanced glycolysis and an altered cytokine secretion (interleukin-6 P<0.0001, interleukin-8/C-X-C motif chemokine ligand 8 P=0.04, and monocyte chemoattractant protein-1/chemokine ligand 2 P=0.01). Furthermore, treatment of atherosclerotic-MSCs with the reactive oxygen species scavenger N-acetyl-l-cysteine reduced the levels of interleukin-6, interleukin-8/C-X-C motif chemokine ligand 8, and monocyte chemoattractant protein-1/chemokine ligand 2 in the MSC secretome and improved MSCs immunosuppressive capacity (P=0.03). CONCLUSIONS: An impaired mitochondrial function of atherosclerotic-MSCs underlies their altered secretome and reduced immunopotency. Interventions aimed at restoring the mitochondrial function of atherosclerotic-MSCs improve their in vitro immunosuppressive ability and may translate into enhanced therapeutic efficiency.
RATIONALE: Mesenchymal stromal cells (MSCs) are promising therapeutic strategies for coronary artery disease; however, donor-related variability in cell quality is a main cause of discrepancies in preclinical studies. In vitro, MSCs from individuals with coronary artery disease have reduced ability to suppress activated T-cells. The mechanisms underlying the altered immunomodulatory capacity of MSCs in the context of atherosclerosis remain elusive. OBJECTIVE: The aim of this study was to assess the role of mitochondrial dysfunction in the impaired immunomodulatory properties of MSCs from patients with atherosclerosis. METHODS AND RESULTS: Adipose tissue-derived MSCs were isolated from atherosclerotic (n=38) and nonatherosclerotic (n=42) donors. MSCs:CD4+T-cell suppression was assessed in allogeneic coculture systems. Compared with nonatherosclerotic-MSCs, atherosclerotic-MSCs displayed higher levels of both intracellular (P=0.006) and mitochondrial (P=0.03) reactive oxygen species reflecting altered mitochondrial function. The increased mitochondrial reactive oxygen species levels of atherosclerotic-MSCs promoted a phenotypic switch characterized by enhanced glycolysis and an altered cytokine secretion (interleukin-6 P<0.0001, interleukin-8/C-X-C motif chemokine ligand 8 P=0.04, and monocyte chemoattractant protein-1/chemokine ligand 2 P=0.01). Furthermore, treatment of atherosclerotic-MSCs with the reactive oxygen species scavenger N-acetyl-l-cysteine reduced the levels of interleukin-6, interleukin-8/C-X-C motif chemokine ligand 8, and monocyte chemoattractant protein-1/chemokine ligand 2 in the MSC secretome and improved MSCs immunosuppressive capacity (P=0.03). CONCLUSIONS: An impaired mitochondrial function of atherosclerotic-MSCs underlies their altered secretome and reduced immunopotency. Interventions aimed at restoring the mitochondrial function of atherosclerotic-MSCs improve their in vitro immunosuppressive ability and may translate into enhanced therapeutic efficiency.
Authors: Kelli I Korski; Dieter A Kubli; Bingyan J Wang; Farid G Khalafalla; Megan M Monsanto; Fareheh Firouzi; Oscar H Echeagaray; Taeyong Kim; Robert M Adamson; Walter P Dembitsky; Åsa B Gustafsson; Mark A Sussman Journal: Stem Cells Date: 2019-01-30 Impact factor: 6.277
Authors: Lauren Boland; Laura Melanie Bitterlich; Andrew E Hogan; James A Ankrum; Karen English Journal: Front Immunol Date: 2022-07-04 Impact factor: 8.786
Authors: Lauren K Boland; Anthony J Burand; Devlin T Boyt; Hannah Dobroski; Lin Di; Jesse N Liszewski; Michael V Schrodt; Maria K Frazer; Donna A Santillan; James A Ankrum Journal: Front Immunol Date: 2019-05-10 Impact factor: 7.561
Authors: Won Dong Yu; Yu Jin Kim; Min Jeong Cho; Gi Jin Kim; Soon Ha Kim; Myung Joo Kim; Jung Jae Ko; Jae Ho Lee Journal: Int J Mol Sci Date: 2021-05-11 Impact factor: 5.923