Le Courrier de la Transplantation - Vol. XV - n° 4 - octobre-novembre-décembre 2015170

Mesenchymal stem cells as immune cells Application to inflammatory diseasesImmunomodulation par les cellules souches mésenchymateuses Application aux maladies inflammatoires C. Jorgensen*

* Directeur de l’Institut de recherche de médecine

régénératrice et de biothérapie, directeur

de l’unité Inserm U  1183, hôpital Lapeyronie, CHRU, Montpellier.

Multipotent mesenchymal stromal cells or mesenchymal stem cells (MSCs) are adult stem cells exhibiting functional properties that

have opened the way for cell-based clinical therapies. Primarily, their capacity for multilineage diff erentiation has been explored in a number of strategies for skeletal tissue regeneration (1). More recently, MSCs have been reported to exhibit immunosuppressive as well as healing properties, to improve angiogenesis and to prevent apoptosis or fi brosis through the secretion of paracrine mediators. This has led to the development of innovative applications for the treatment of infl ammatory and degenerative rheumatic diseases including rheumatoid arthritis (RA), osteoarthritis (OA) as well as bone and cartilage genetic disorders. To date, most of the data have been obtained in pre-clinical models. However, some clinical applications have been initiated, focusing on the potential of MSCs for skeletal tissue repair. New developments on the therapeutic applications of MSCs aim at interfering with immune responses of patients in various infl ammatory auto-immune disorders, or inhibiting the progress of clinical symptoms in degenerative diseases. Besides current researches on the understanding of the mechanisms

regulating the therapeutic efficacy of MSCs, more knowledge on migration, biodistribution, survival and safety of MSCs, after systemic infusion or local implantation, must be gained for generalized therapeutic use in rheumatic diseases.

Immunomodulatory eff ects of MSCs

In addition to the properties mentioned above, MSCs are potent immunomodulatory agents with anti-proliferative and anti-infl ammatory capacities. MSC-mediated immunomodulation requires priming by immune cells through secretion of the pro-infl ammatory cytokines interferon (IFN)-γ with tumour necrosis factor (TNF)-α or IL-1β. After activation, immunosuppressive activity is mainly mediated via the secretion of soluble factors. Proposed mechanisms include indoleamine 2,3-dioxygenase (IDO) or nitric oxide synthase (iNOS) activities, secretion of human leukocyte antigen (HLA)-G, prostaglandin (PGE2) [2, 3], tumour necrosis factor-stimulated gene (TSG)-6 (4) . A recent study also confi rmed the role of heme oxydase (HO-1) in promoting the generation of Tr1 and Th3 regulatory T cells and the production of IL-10 (5) These soluble mediators can

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» Multipotent mesenchymal stromal cells (mesenchymal stem cells) [MSCs] are adult stem cells exhibiting functional properties that have been explored for skeletal tissue regeneration. MSCs also exhibit immunosuppressive as well as healing capacities, improving angiogenesis and preventing apoptosis or fi brosis through the secretion of paracrine mediators. This could be useful in the treatment of infl ammatory and degenerative rheumatic diseases and cartilage genetic disorders. Some clinical applications have also been obtained for skeletal tissue repair. Further investigation of the effi cacy and safety of MSCs is needed for current therapeutic uses.

Keywords: Mesenchymal stem cells - Immunomodulation - Healing.

Les cellules souches mésenchymateuses (MSCs) sont des cellules-souches adultes dont les capacités fonctionnelles ont été utilisées pour la régénération de tissus musculosquelettiques et cartilagineux. Elles ont également des propriétés immunomodulatrices et de cicatrisation (augmentation de l’angiogénèse, inhibition de la fi brogénèse, inhibition de l’apoptose) par le biais de sécrétions paracrines. Ces propriétés peuvent être utilisées dans le traitement des maladies ostéoarticulaires et cartilagineuses infl ammatoires ou dégénératives, et les premiers résultats cliniques sont encourageants. Des recherches supplémentaires doivent être réalisées pour évaluer leur effi cacité et leur sécurité en pratique clinique.

Mots-clés : Cellules souches mésenchymateuses - Immuno-modulation - Cicatrisation.

D o s s i e r

La médecine régénérative

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Le Courrier de la Transplantation - Vol. XV - n° 4 - octobre-novembre-décembre 2015 171

inhibit both T and B cell proliferation and function. MSCs inhibited antigen-dependent proliferation and differentiation to plasma cells of follicular and marginal zone B cells in vitro. This inhibitory eff ect was dependent on IFNγ and was mediated by cell-to-cell contact, involving the programmed cell death 1 (PD-1)/PD pathway (6). MSCs also suppress the generation of dendritic cells (DC) from monocytes or progenitor cells isolated from bone marrow, and inhibit their maturation and function (7, 8). Finally, it was shown recently that MSCs inhibit Th17 cell diff erentiation and induce fully diff erentiated Th17 cells to exert a T cell regulatory phenotype (9).

Immunomodulation of infl ammatory arthritis

The potential of MSCs to modulate the host immune response, mainly by inhibiting the proliferation of

T lymphocytes, introduced the possibility that they might be effective in inflammatory arthritis where the T cell response is prominent. Studies using the collagen-induced arthritis (CIA) experimental mouse model reported improvement of clinical and biological scores after injection of MSCs derived from bone marrow or adipose tissue (10). We and others have, however, reported contradictory results with absence of therapeutic benefi t after MSC infusion and even exacerbation of arthritis . More recently, our group has shown that IL-6-dependent PGE2 secretion by primary murine MSCs inhibits local infl ammation in experimental arthritis in a time-dependent fashion. We also showed that therapeutic eff ect of MSCs was observed during a narrow window of MSC application, suggesting that discrepancy between studies may be related to the time of injection and/or the immune status of animals at that time. ■

1. Vinatier C, Mrugala D, Jorgensen C, Guicheux J, Noël D. Cartilage engineering: a crucial combination of cells, biomaterials and biofactors. Trends Biotechnol 2009;27(5):307-14.

2. Bouffi C, Bony C, Courties G, Jorgensen C, Noël D. IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local infl ammation in experimental arthritis. PLoS One 2010;5(12):e14247.

3. Yanez R, Oviedo A, Aldea M, Bueren JA, Lamana ML. Prostaglandin E2 plays a key role in the immunosuppressive properties of adipose and bone marrow tissue-derived mesenchymal stromal cells. Exp Cell Res 2010;316(19):3109-23.

4. Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D.

Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther 2010;1(1):2.

5. Mougiakakos D, Jitschin R, Johansson CC, Okita R, Kiessling R, Le Blanc K. The impact of infl ammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. Blood 2011;117(18):4826-35.

6. Schena F, Gambini C, Gregorio A et al. Interferon-gamma-dependent inhibition of B cell activation by bone marrow-derived mesenchymal stem cells in a murine model of systemic lupus erythematosus. Arthritis Rheum 2010;62(9);2776-86.

7. Djouad F, Charbonnier LM, Bouffi C et al. Mesenchymal stem cells inhibit the diff erentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells 2007;25(8):2025-32.

8. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 2006;177(4):2080-7.

9. Ghannam S, Pène J, Moquet-Torcy G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell diff erentiation and function and induce a T regulatory cell phenotype. J Immunol 2010:185(1):302-12.

10. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-infl ammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One 2010;5(4):e10088.

R é f é r e n c e s b i b l i o g r a p h i q u e s

C. Jorgensen déclare ne pas avoir de liens d’intérêts.

Grandir ensemble, c’est magique…

Continuons en 2016 !

Bonnes fêtes de fin d’année à tous Claudie Damour-Terrasson Directeur de la publication

Mesenchymal stem cells as immune cells Application to infl ammatory diseases

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