title: Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses.
abstract: Mesenchymal stromal cells (MSCs) support hematopoiesis and exert immunoregulatory activities. Here, we analyzed the functional outcome of the interactions between MSCs and monocytes/macrophages. We showed that MSCs supported the survival of monocytes that underwent differentiation into macrophages, in the presence of macrophage colony-stimulating factor. However, MSCs skewed their polarization toward a peculiar M2-like functional phenotype (M(MSC) ), through a prostaglandin E2-dependent mechanism. M(MSC) were characterized by high expression of scavenger receptors, increased phagocytic capacity, and high production of interleukin (IL)-10 and transforming growth factor-β. These cytokines contributed to the immunoregulatory properties of M(MSC) , which differed from those of typical IL-4-induced macrophages (M2). In particular, interacting with activated natural killer (NK) cells, M(MSC) inhibited both the expression of activating molecules such as NKp44, CD69, and CD25 and the production of IFNγ, while M2 affected only IFNγ production. Moreover, M(MSC) inhibited the proliferation of CD8(+) T cells in response to allogeneic stimuli and induced the expansion of regulatory T cells (Tregs). Toll-like receptor engagement reverted the phenotypic and functional features of M(MSC) to those of M1 immunostimulatory/proinflammatory macrophages. Overall our data show that MSCs induce the generation of a novel type of alternatively activated macrophages capable of suppressing both innate and adaptive immune responses. These findings may help to better understand the role of MSCs in healthy tissues and inflammatory diseases including cancer, and provide clues for novel therapeutic approaches. Stem Cells 2016;34:1909-1921.
authors.affiliation: Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Chiossone
authors.affiliation: Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Romana
authors.initials: R
authors.lastname: Conte
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Spaggiari
authors.affiliation: Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Serra
authors.affiliation: Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bellora
authors.affiliation: Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Becchetti
authors.affiliation: Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Andaloro
authors.affiliation: Department of Immunology, Ospedale Pediatrico Bambino Gesù, Roma, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy.|Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bottino
mesh_terms: D056704:Adaptive Immunity; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D002648:Child; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009000:Monocytes / Q000166:cytology; D050378:T-Lymphocytes, Regulatory
chemical_list: D007371:Interferon-gamma
keywords: Macrophages; Mesenchymal stromal cells; NK cells; PGE2; T cells