Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals.
Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, they have gained further interest after demonstration of an immunosuppressive role. In this study, we investigated whether in vivo injection of MSCs could display side effects related to systemic immunosuppression favoring tumor growth. We first showed in vitro that the murine C3H10T1/2 (C3) MSC line and primary MSCs exhibit immunosuppressive properties in mixed lymphocyte reaction. We demonstrated that this effect is mediated by soluble factors, secreted only on "activation" of MSCs in the presence of splenocytes. Moreover, the immunosuppression is mediated by CD8+ regulatory cells responsible for the inhibition of allogeneic lymphocyte proliferation. We then demonstrated that the C3 MSCs expressing the human bone morphogenetic protein 2 (hBMP-2) differentiation factor were not rejected when implanted in various allogeneic immunocompetent mice and were still able to differentiate into bone. Importantly, using a murine melanoma tumor model, we showed that the subcutaneous injection of B16 melanoma cells led to tumor growth in allogeneic recipients only when MSCs were coinjected. Although the potential side effects of immunosuppression induced by MSCs have to be considered in further clinical studies, the usefulness of MSCs for various therapeutic applications still remains of great interest.
Djouad
Farida
F
INSERM U475, 99 rue Puech Villa, 34197 Montpellier cedex 5, France.
Plence
Pascale
P
Bony
Claire
C
Tropel
Philippe
P
Apparailly
Florence
F
Sany
Jacques
J
Noël
Danièle
D
Jorgensen
Christian
C
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D002455:Cell Division; D045744:Cell Line, Tumor; D006801:Humans; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008545:Melanoma / Q000473:pathology* / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects*; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D013154:Spleen / Q000166:cytology; D016212:Transforming Growth Factor beta
C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta