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

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Abstract

Background

The 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).

Methods

CIA 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 (10 ⁶ 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.

Results

Administration 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.

Conclusion

Treatment 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.

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Most cited references 38

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Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans.

Lingyun Sun, Kentaro Akiyama, Huayong Zhang … (2009)

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that, despite the advances in immunosuppressive medical therapies, remains potentially fatal in some patients, especially in treatment-refractory patients. Here, we reported that impairment of bone marrow mesenchymal stem cells (BMMSCs) and their associated osteoblastic niche deficiency contribute in part to the pathogenesis of SLE-like disease in MRL/lpr mice. Interestingly, allogenic BMMSC transplantation (MSCT) is capable of reconstructing the bone marrow osteoblastic niche and more effectively reverses multiorgan dysfunction when compared with medical immunosuppression with cyclophosphamide (CTX). At the cellular level, MSCT, not CTX treatment, was capable to induce osteoblastic niche reconstruction, possibly contributing to the recovery of regulatory T-cells and reestablishment of the immune homeostasis. On the basis of the promising clinical outcomes in SLE mice, we treated four CTX/glucocorticoid treatment-refractory SLE patients using allogenic MSCT and showed a stable 12-18 months disease remission in all treated patients. The patients benefited an amelioration of disease activity, improvement in serologic markers and renal function. These early evidences suggest that allogenic MSCT may be a feasible and safe salvage therapy in refractory SLE patients.

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IL-6-Dependent PGE2 Secretion by Mesenchymal Stem Cells Inhibits Local Inflammation in Experimental Arthritis

Carine Bouffi, Claire Bony, Gabriel Courties … (2010)

Background Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSC) are intensively studied for various clinical applications. Although it has been shown in vitro that the immunomodulatory effect of MSCs mainly occurs through the secretion of soluble mediators, the mechanism is still not completely understood. The aim of the present study was to better understand the mechanisms underlying the suppressive effect of MSCs in vivo, using cells isolated from mice deficient in the production of inducible nitric oxide synthase (iNOS) or interleukin (IL)-6 in the murine model of collagen-induced arthritis. Principal Findings In the present study, we show that primary murine MSCs from various strains of mice or isolated from mice deficient for iNOS or IL-6 exhibit different immunosuppressive potential. The immunomodulatory function of MSCs was mainly attributed to IL-6-dependent secretion of prostaglandin E2 (PGE2) with a minor role for NO. To address the role of these molecules in vivo, we used the collagen-induced arthritis as an experimental model of immune-mediated disorder. MSCs effectively inhibited collagen-induced inflammation during a narrow therapeutic window. In contrast to wild type MSCs, IL-6-deficient MSCs and to a lesser extent iNOS-deficient MSCs were not able to reduce the clinical signs of arthritis. Finally, we show that, independently of NO or IL-6 secretion or Treg cell induction, MSCs modulate the host response by inducing a switch to a Th2 immune response. Significance Our data indicate that MSCs mediate their immunosuppressive effect via two modes of action: locally, they reduce inflammation through the secretion of anti-proliferative mediators, such as NO and mainly PGE2, and systemically they switch the host response from a Th1/Th17 towards a Th2 immune profile.

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Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis.

Malika Trad, Jean-Francis Maillefert, Pierre Miossec … (2012)

From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA. Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg). Compared to controls, levels of Th17 cells (CD4+IL-17+) were increased and Treg cells (CD4+CD25(high) FoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients. This study demonstrates for the first time that inhibition of IL-6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA. Copyright © 2012 by the American College of Rheumatology.

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Author and article information

Contributors

Elena Gonzalo-Gil: elena.gonzalogil@yale.edu

María J. Pérez-Lorenzo: mariapl_za@yahoo.es

María Galindo: mgalindo@h12o.es

Rafael Díaz de la Guardia: rdiaz@carrerasresearch.org

Belén López-Millán: mariabelenlopezmillan@gmail.com

Clara Bueno: cbueno@carrerasresearch.org

Pablo Menéndez: pmenendez@carrerasresearch.org

José L. Pablos: jlpablos@h12o.es

Gabriel Criado:

ORCID: http://orcid.org/0000-0003-4824-0890

gcriado@h12o.es

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res. Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 1 April 2016

Publication date PMC-release: 1 April 2016

Publication date (Print): 2016

Volume: 18

Electronic Location Identifier: 77

Affiliations

[ ]Inflammatory and Autoimmune Diseases Group, Hospital 12 de Octubre Research Institute, Madrid, Spain

[ ]Rheumatology Department, Hospital 12 de Octubre, Madrid, Spain

[ ]Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Barcelona, Spain

[ ]Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

[ ]Inflammatory and Autoimmune Diseases Group, Hospital 12 de Octubre Research Center, Avenida de Córdoba s/n. 28041, Madrid, Spain

Author information

Gabriel Criado http://orcid.org/0000-0003-4824-0890

Article

Publisher ID: 979

DOI: 10.1186/s13075-016-0979-0

PMC ID: 4818397

PubMed ID: 27036118

SO-VID: 130024e4-2461-478e-95d6-68ed84751aec

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 November 2015

Date accepted : 18 March 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III (ES)-FEDER;

Award ID: PI11/00028

Award Recipient : Gabriel Criado

Funded by: Instituto de Salud Carlos III-FEDER

Award ID: PI14/01119

Award ID: CP13/00014

Award ID: CP13/00011

Award ID: RETICS RD12/009 RIER

Award Recipient : Clara Bueno Gabriel Criado

Funded by: Obra Social La Caixa-Fundació Josep Carreras

Funded by: FundRef http://dx.doi.org/10.13039/501100002809, Generalitat de Catalunya;

Award ID: SGR330

Award Recipient : Pablo Menéndez

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ScienceOpen disciplines: Orthopedics

Keywords: arthritis,human embryonic stem cell-derived mesenchymal stromal cells,t cells,cytokines,indoleamine 2,3 dioxygenase

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ScienceOpen disciplines: Orthopedics

Keywords: arthritis, human embryonic stem cell-derived mesenchymal stromal cells, t cells, cytokines, indoleamine 2,3 dioxygenase

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

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Most cited references 38

Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans.

IL-6-Dependent PGE2 Secretion by Mesenchymal Stem Cells Inhibits Local Inflammation in Experimental Arthritis

Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis.

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