title: Human Mesenchymal Stem Cell-Educated Macrophages Are a Distinct High IL-6-Producing Subset that Confer Protection in Graft-versus-Host-Disease and Radiation Injury Models.
abstract: Mesenchymal stem cells (MSCs) have immunosuppressive and tissue repair properties, but clinical trials using MSCs to prevent or treat graft-versus-host disease (GVHD) have shown mixed results. Macrophages (MØs) are important regulators of immunity and can promote tissue regeneration and remodeling. We have previously shown that MSCs can educate MØs toward a unique anti-inflammatory immunophenotype (MSC-educated MØs [MEMs]); however, their implications for in vivo models of inflammation have not been studied yet. We now show that in comparison with MØs, MEMs have increased expression of the inhibitory molecules PD-L1, PD-L2, in addition to markers of alternatively activated MØs: CD206 and CD163. RNA-Seq analysis of MEMs, as compared with MØs, show a distinct gene expression profile that positively correlates with multiple pathways important in tissue repair. MEMs also show increased expression of IL-6, transforming growth factor-β, arginase-1, CD73, and decreased expression of IL-12 and tumor necrosis factor-α. We show that IL-6 secretion is controlled in part by the cyclo-oxygenase-2, arginase, and JAK1/STAT1 pathway. When tested in vivo, we show that human MEMs significantly enhance survival from lethal GVHD and improve survival of mice from radiation injury. We show these effects could be mediated in part through suppression of human T cell proliferation and may have attenuated host tissue injury in part by enhancing murine fibroblast proliferation. MEMs are a unique MØ subset with therapeutic potential for the management of GVHD and/or protection from radiation-induced injury.
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Myriam N
authors.initials: MN
authors.lastname: Bouchlaka
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina; Duke Center of Genomic and Computational Biology, Durham, North Carolina.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Moffitt
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Jaehyup
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: John A
authors.initials: JA
authors.lastname: Kink
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Debra D
authors.initials: DD
authors.lastname: Bloom
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina; Duke Center of Genomic and Computational Biology, Durham, North Carolina.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Love
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina; Duke Center of Genomic and Computational Biology, Durham, North Carolina.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dave
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. Electronic address: ccapitini@pediatrics.wisc.edu.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Capitini
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000276:immunology*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000628:therapy*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D011832:Radiation Injuries / Q000628:therapy*
chemical_list: D015850:Interleukin-6
keywords: Graft-versus-host disease (GVHD); IL-6; MSC-educated macrophages (MEMs); Macrophages; Mesenchymal stem cells (MSCs); Radiation injury