Human embryonic stem cell-derived mesenchymal stromal cells ameliorate collagen-induced arthritis by inducing host-derived indoleamine 2,3 dioxygenase

Abstract

BackgroundThe immunosuppressive and anti-inflammatory properties of mesenchymal stromal cells (MSC) have prompted their therapeutic application in several autoimmune diseases, including rheumatoid arthritis. Adult MSC are finite and their clinical use is restricted by the need for long-term expansion protocols that can lead to genomic instability. Inhibition of Smad2/3 signaling in human pluripotent stem cells (hPSC) provides an infinite source of MSC that match the phenotype and functional properties of adult MSC. Here, we test the therapeutic potential of hPSC-MSC of embryonic origin (embryonic stem cell-derived mesenchymal stromal cells, hESC-MSC) in the experimental model of collagen-induced arthritis (CIA).MethodsCIA was induced in DBA/1 mice by immunization with type II collagen (CII) in Complete Freund’s Adjuvant (CFA). Mice were treated with either a single dose (106 cells/mouse) of hESC-MSC on the day of immunization (prophylaxis) or with three doses of hESC-MSC every other day starting on the day of arthritis onset (therapy). Arthritis severity was evaluated daily for six weeks and ten days, respectively. Frequency of Treg (FoxP3+), Th1 (IFNγ+) and Th17 (IL17+) CD4+ T cells in inguinal lymph nodes (ILN) was quantified by flow cytometry. Serum levels of anti-CII antibodies were determined by ELISA. Detection of hESC-MSC and quantification of murine and human indoleamine 2,3 dioxygenase (IDO1) expression was performed by quantitative real-time PCR. Statistical differences were analyzed by ANOVA and the Mann-Whitney U test.ResultsAdministration of hESC-MSC to mice with established arthritis reduced disease severity compared to control-treated mice. Analysis of CD4 T cell populations in treated mice showed an increase in FoxP3+ Treg and IFNγ+ Th1 cells but not in Th17 cells in the ILN. Anti-CII antibody levels were not affected by treatment. Migration of hESC-MSC to the ILN in treated mice was associated with the induction of murine IDO1.ConclusionTreatment with hESC-MSC ameliorates CIA by inducing IFNγ+ Th1 cells and IDO1 in the host. Thus, hESC-MSC can provide an infinite cellular source for treatment of rheumatoid arthritis.

TSG-6 Secreted by Human Adipose Tissue-derived Mesenchymal Stem Cells Ameliorates DSS-induced colitis by Inducing M2 Macrophage Polarization in Mice

“…Consistent with these findings, recent investigations have revealed that MSCs regulate the inflammatory processes through various soluble factors such as indoleamine 2,3-dioxygenase, TGF-β, prostaglandin E2 (PGE2), and TSG-6 31, 46–48 . Among these, TSG-6 has been shown to be pivotal for the anti-inflammatory effects of MSCs in corneal inflammation, severe burn injury, acute lung injury, acute peritonitis, pancreatitis, and IBD 13, 16, 17, 47, 49, 50 .…”

Extracellular vesicles derived from human embryonic stem cell‐MSCs ameliorate cirrhosis in thioacetamide‐induced chronic liver injury

“…In addition, it was demonstrated that human ES-MSCs can inhibit CD83 up-regulation and IL-12p70 secretion from dendritic cells and increase T-reg cell populations after induction by IL-2 . The therapeutic potentials of ES-and iPS-MSCs have been investigated in many animal models such as inflammatory bowel disease (Sanchez et al, 2011), fistulizing Crohn's disease (Ferrer et al, 2016), experimental autoimmune encephalitis (Wang et al, 2014), cardiac remodeling and dysfunction (Liang et al, 2017), arthritis (Gonzalo-Gil et al, 2016), lupus nephritis (Thiel et al, 2015), cardiomyopathy , diabetes (Hajizadeh-Saffar et al, 2015) and pulmonary arterial hypertension . We also reported the therapeutic effect of human ES-MSC on acute hepatic failure (Lotfinia et al, 2016) and lethal fulminant hepatic failure models (Moslem, Valojerdi, Pournasr, Muhammadnejad & Baharvand, 2013 (Feng, Mantesso, De Bari, Nishiyama & Sharpe, 2011) and autophagy (Jung et al, 2013) through their secretome Huang et al, 2016;Konala et al, 2016).…”

Concise Review: Mesenchymal Stem Cells Derived from Human Pluripotent Cells, an Unlimited and Quality-Controllable Source for Therapeutic Applications

“…Transplanted ps‐MSCs remarkably attenuate severe hind‐limb ischemia in mice via direct differentiation and paracrine mechanisms and provide a stronger therapeutic effect than BM‐MSCs on vascular and muscle regeneration . Moreover, ps‐MSCs reduce the symptoms in mice with a variety of inflammatory and autoimmune disease such as allergy airway inflammation , lupus, uveitis, collagen‐induced arthritis , and inflammatory bowel disease (IBD) . ps‐MSCs improve clinical abnormalities in IBD by promoting intestinal epithelial cell proliferation, increasing Lgr5 + intestinal stem cells, and stimulating intestinal angiogenesis .…”