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.

Canine adipose tissue-derived mesenchymal stem cells pre-treated with TNF-alpha enhance immunomodulatory effects in inflammatory bowel disease in mice

“…Here, we also showed that TNF-α-stimulated cAT-MSCs released significantly higher concentrations of TSG-6 (2.5-fold) and PGE2 (3-fold), relative to naive cAT-MSCs. TSG-6 and PGE 2 are well-known immunomodulatory factors secreted from human and canine MSCs, and recent studies have demonstrated that these factors play important roles in ameliorating atopic dermatitis, rheumatoid arthritis, acute pancreatitis, and IBD Kim et al, 2015;Mao et al, 2017;Shin et al, 2016;Song et al, 2017a). Consistent with these studies, our results indicated that cAT-MSCs stimulated with TNF-α further reduced DSS-or DNBS-induced colitis by releasing higher concentrations of TSG-6 and PGE 2 .…”

“…Melief et al demonstrated that human MSCs promote the transition of monocytes into CD206 + M2 macrophages, and consequently increase Foxp3 + regulatory T cells (Melief et al, 2013). In addition, recent studies have revealed that soluble factors (such as TSG-6 and PGE 2 ) released from human MSCs could promote the M2 macrophage phenotype and reduce inflammation in mouse models of rheumatoid arthritis, wound healing, and IBD (Shin et al, 2016;Song et al, 2017b;Zhang et al, 2010). Additionally, we previously demonstrated that TSG-6 released from canine MSCs can induce M2 macrophage phenotypic changes in vitro and in vivo .…”

Inflammasomes contributing to inflammation in arthritis

“…The severity of arthritis clinical score showed a positive correlation with NLRP3 levels in synovial tissue, 66 and clinical features of arthritic disease could be inhibited by suppression of the NLRP3 inflammasome in macrophages. 67 Furthermore, in an adjuvant-induced arthritis model in rats, upregulation of NLRP3 inflammasome components was observed in fibroblast-like cells isolated from the synovium. 68,69 These results are in line with results obtained in mice lacking the A20/Tnfaip3 gene, which predispose them to an RA-like disease.…”

Mesenchymal Stem Cells from Chronic Pancreatitis Patients Show Comparable Potency Compared to Cells from Healthy Donors

“…Meanwhile, MSCs have been shown to secrete angiogenic paracrine factors such as vascular endothelial growth factor (VEGF), hepatocytes growth factor (HGF), transforming growth factor β (TGF‐β), and matrix metalloproteinase, which contribute to the establishment of a graft vascular network . MSCs also possess a distinctive array of immunosuppressive characteristics, which was observed in many disease models including autoimmune encephalomyelitis , multiple sclerosis , and arthritis . Studies have demonstrated that MSCs can modulate the function of T and B lymphocytes , natural killer cells , and regulatory T cells .…”