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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.
Highlights
The immunosuppressive and anti-inflammatory properties of mesenchymal stromal cells (MSC) have prompted their therapeutic application in several autoimmune diseases, including rheumatoid arthritis
Administration of hESC-MSC in mice with established disease reduced the severity of arthritis and increased the frequency of regulatory T cells (Treg) and T helper (Th)1 cells without affecting Th17 cells. hESC-MSC administered to mice with collagen-induced arthritis (CIA) migrated to draining lymph nodes and induced indoleamine 2 (IDO1) expression
Results hESC-MSC ameliorate established collagen-induced arthritis To test the ability of hESC-MSC to modulate the progression of arthritis after type II collagen (CII) immunization, DBA/1 mice were treated prophylactically with 106 cells at the time of immunization, and the evolution of arthritis was assessed daily for 6 weeks
Summary
The immunosuppressive and anti-inflammatory properties of mesenchymal stromal cells (MSC) have prompted their therapeutic application in several autoimmune diseases, including rheumatoid arthritis. Human PSC represent an infinite source for MSC, and hPSC-MSC display an identical phenotype, functional properties, and in vitro and in vivo immunosuppressive and anti-inflammatory features compared to adult bone-marrow-derived or cord-blood-derived MSC, as demonstrated in experimental models of acute inflammation in vivo when administered prophylactically [6]. These findings prompted us to investigate the potential therapeutic use of hESCMSC in the setting of the chronic inflammatory model of CIA. Administration of hESC-MSC in mice with established disease reduced the severity of arthritis and increased the frequency of Treg and T helper (Th) cells without affecting Th17 cells. hESC-MSC administered to mice with CIA migrated to draining lymph nodes and induced IDO1 expression
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