title: Therapeutic effects and mechanism of conditioned media from human mesenchymal stem cells on anti-GBM glomerulonephritis in WKY rats.
abstract: Recent studies have demonstrated that conditioned media derived from mesenchymal stem cells (MSC-CM) have therapeutic effects in various experimental diseases. However, the therapeutic mechanism is not fully understood. In the present study, we investigated the therapeutic effects and mechanism of MSC-CM in experimental antiglomerular basement membrane glomerulonephritis. We administered either MSC-CM or vehicle from day 0 to day 10 after the induction of nephrotoxic serum nephritis in Wistar-Kyoto rats. In vitro, we analyzed the effects of MSC-CM on TNF-α-mediated cytokine production in cultured normal human mesangial cells, proximal tubular (HK-2) cells, human umbilical vein endothelial cells, and monocytes (THP-1 and peripheral blood mononuclear cells). Compared with vehicle treatment, MSC-CM treatment improved proteinuria and renal dysfunction. Histologically, MSC-CM-treated rats had reduced crescent formation and glomerular ED1(+) macrophage infiltration and increased glomerular ED2(+) macrophage infiltration. Increased serum monocyte chemoattractant protein (MCP)-1 levels were observed in MSC-CM-treated rats. Renal cortical mRNA expression levels of proinflammatory cytokines, such as TNF-α and IL-6, and of the T helper cell 1 cytokine interferon-γ were greatly decreased by MSC-CM treatment. In vitro, pretreatment with MSC-CM blocked TNF-α-mediated IL-8 release in normal human mesangial cells and HK-2 cells. TNF-α-mediated MCP-1 release was enhanced by pretreatment with MSC-CM in human umbilical vein endothelial cells and HK-2 cells and was strikingly enhanced in THP-1 cells. Stimulation of peripheral blood mononuclear cells with a combination of MCP-1 and IL-4 enhanced the expression of M2-associated genes compared with IL-4 alone. We demonstrated that MSC-CM had therapeutic effects in experimental antiglomerular basement membrane glomerulonephritis that were mediated through anti-inflammatory effects that were partly due to acceleration of M2 macrophage polarization, which might be mediated by MCP-1 enhancement.
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Ken
authors.initials: K
authors.lastname: Iseri
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and iyoda@med.showa-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iyoda
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohtaki
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Kei
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Wada
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Taihei
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Saito
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Kei
authors.initials: K
authors.lastname: Hihara
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Shohei
authors.initials: S
authors.lastname: Tachibana
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Kazuho
authors.initials: K
authors.lastname: Honda
authors.affiliation: Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; and.
authors.forename: Takanori
authors.initials: T
authors.lastname: Shibata
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015847:Interleukin-4 / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D017077:Culture Media, Conditioned; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4
keywords: Wistary-Kyoto; conditioned media; glomerular basement membrane; glomerulonephritis; macrophages; monocyte chemoattractant protein-1; stem cells