title: Serum-starved adipose-derived stromal cells ameliorate crescentic GN by promoting immunoregulatory macrophages.
abstract: Mesenchymal stromal cells (MSCs) derived from adipose tissue have immunomodulatory effects, suggesting that they may have therapeutic potential for crescentic GN. Here, we systemically administered adipose-derived stromal cells (ASCs) in a rat model of anti-glomerular basement membrane (anti-GBM) disease and found that this treatment protected against renal injury and decreased proteinuria, crescent formation, and infiltration by glomerular leukocytes, including neutrophils, CD8(+) T cells, and CD68(+) macrophages. Interestingly, ASCs cultured under low-serum conditions (LASCs), but not bone marrow-derived MSCs (BM-MSCs), increased the number of immunoregulatory CD163(+) macrophages in diseased glomeruli. Macrophages cocultured with ASCs, but not with BM-MSCs, adopted an immunoregulatory phenotype. Notably, LASCs polarized macrophages into CD163(+) immunoregulatory cells associated with IL-10 production more efficiently than ASCs cultured under high-serum conditions. Pharmaceutical ablation of PGE2 production, blocking the EP4 receptor, or neutralizing IL-6 in the coculture medium all significantly reversed this LASC-induced conversion of macrophages. Furthermore, pretreating LASCs with aspirin or cyclooxygenase-2 inhibitors impaired the ability of LASCs to ameliorate nephritogenic IgG-mediated renal injury. Taken together, these results suggest that LASCs exert renoprotective effects in anti-GBM GN by promoting the phenotypic conversion of macrophages to immunoregulatory cells, suggesting that LASC transfer may represent a therapeutic strategy for crescentic GN.
authors.affiliation: Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Furuhashi
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuboi
authors.forename: Asuka
authors.initials: A
authors.lastname: Shimizu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Katsuno
authors.forename: Hangsoo
authors.initials: H
authors.lastname: Kim
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Saka
authors.forename: Takenori
authors.initials: T
authors.lastname: Ozaki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sado
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000628:therapy*; D018929:Cell Culture Techniques; D016895:Culture Media, Serum-Free; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D056747:Immunomodulation; D008264:Macrophages / Q000276:immunology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology; D051381:Rats; D011921:Rats, Inbred WKY; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology
chemical_list: D016895:Culture Media, Serum-Free; D016207:Cytokines