Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis

• Published in: Cell death & disease Vol. 7; no. 12; p. e2524
• Main Authors: Shin, Tae-Hoon, Kim, Hyung-Sik, Kang, Tae-Wook, Lee, Byung-Chul, Lee, Hwa-Yong, Kim, Yoon-Jin, Shin, Ji-Hee, Seo, Yoojin, Won Choi, Soon, Lee, Seunghee, Shin, Kichul, Seo, Kwang-Won, Kang, Kyung-Sun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.12.2016; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/100; 13/31; 13/89; 14/19; 631/250/2504/342; 631/250/256/2177; 64/60; 692/699/249/1313/498; 692/700/565/251; 82/80; Administration, Intravenous; Animals; Antibodies; Arthritis, Experimental - pathology; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - therapy; Biochemistry; Biomedical and Life Sciences; Caspase 1 - metabolism; Cell Adhesion Molecules - metabolism; Cell Biology; Cell Culture; Cell Polarity - drug effects; Cyclooxygenase 2 - metabolism; Disease Models, Animal; Feedback, Physiological - drug effects; Female; Fetal Blood - cytology; Humans; Immunology; Inflammasomes - metabolism; Inflammation; Inflammation Mediators - metabolism; Injections, Intraperitoneal; Interleukin-1beta - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Life Sciences; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - pathology; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - drug effects; Mice; Middle Aged; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Original; original-article; Public health; Rheumatoid arthritis; Stem cells; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.442

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-1 β 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.