title: Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a long-lasting intractable autoimmune disorder, which has become a substantial public health problem. Despite widespread use of biologic drugs, there have been uncertainties in efficacy and long-term safety. Mesenchymal stem cells (MSCs) have been suggested as a promising alternative for the treatment of RA because of their immunomodulatory properties. However, the precise mechanisms of MSCs on RA-related immune cells are not fully elucidated. The aim of this study was to investigate the therapeutic potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) as a new therapeutic strategy for patients with RA and to explore the mechanisms underlying hUCB-MSC-mediated immunomodulation. Mice with collagen-induced arthritis (CIA) were administered with hUCB-MSCs after the onset of disease, and therapeutic efficacy was assessed. Systemic delivery of hUCB-MSCs significantly ameliorated the severity of CIA to a similar extent observed in the etanercept-treated group. hUCB-MSCs exerted this therapeutic effect by regulating macrophage function. To verify the regulatory effects of hUCB-MSCs on macrophages, macrophages were co-cultured with hUCB-MSCs. The tumor necrosis factor (TNF)-α-mediated activation of cyclooxygenase-2 and TNF-stimulated gene/protein 6 in hUCB-MSCs polarized naive macrophages toward an M2 phenotype. In addition, hUCB-MSCs down-regulated the activation of nucleotide-binding domain and leucine-rich repeat pyrin 3 inflammasome via a paracrine loop of interleukin-1β signaling. These immune-balancing effects of hUCB-MSCs were reproducible in co-culture experiments using peripheral blood mononuclear cells from patients with active RA. hUCB-MSCs can simultaneously regulate multiple cytokine pathways in response to pro-inflammatory cytokines elevated in RA microenvironment, suggesting that treatment with hUCB-MSCs could be an attractive candidate for patients with treatment-refractory RA.
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Shin
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hyung-Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul, Republic of Korea.
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Kang
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Lee
authors.affiliation: Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hwa-Yong
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul, Republic of Korea.
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Seo
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Soon
authors.initials: S
authors.lastname: Won Choi
authors.affiliation: Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Kichul
authors.initials: K
authors.lastname: Shin
authors.affiliation: Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul, Republic of Korea.
authors.forename: Kwang-Won
authors.initials: KW
authors.lastname: Seo
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.|Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000473:pathology / Q000628:therapy*; D020170:Caspase 1 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000473:pathology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D058847:Inflammasomes; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C513057:Tnfaip6 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D020170:Caspase 1