title: Mesenchymal stem cells: a double-edged sword in regulating immune responses.
abstract: Mesenchymal stem cells (MSCs) have been employed successfully to treat various immune disorders in animal models and clinical settings. Our previous studies have shown that MSCs can become highly immunosuppressive upon stimulation by inflammatory cytokines, an effect exerted through the concerted action of chemokines and nitric oxide (NO). Here, we show that MSCs can also enhance immune responses. This immune-promoting effect occurred when proinflammatory cytokines were inadequate to elicit sufficient NO production. When inducible nitric oxide synthase (iNOS) production was inhibited or genetically ablated, MSCs strongly enhance T-cell proliferation in vitro and the delayed-type hypersensitivity response in vivo. Furthermore, iNOS(-/-) MSCs significantly inhibited melanoma growth. It is likely that in the absence of NO, chemokines act to promote immune responses. Indeed, in CCR5(-/-)CXCR3(-/-) mice, the immune-promoting effect of iNOS(-/-) MSCs is greatly diminished. Thus, NO acts as a switch in MSC-mediated immunomodulation. More importantly, the dual effect on immune reactions was also observed in human MSCs, in which indoleamine 2,3-dioxygenase (IDO) acts as a switch. This study provides novel information about the pathophysiological roles of MSCs.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Ren
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Su
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Cao
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Shou
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: Z-R
authors.initials: ZR
authors.lastname: Yuan
authors.forename: A I
authors.initials: AI
authors.lastname: Roberts
authors.forename: S
authors.initials: S
authors.lastname: Shi
authors.forename: A D
authors.initials: AD
authors.lastname: Le
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D018925:Chemokines; C515188:Cxcr3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse