Mesenchymal stem cells immunosuppressive properties: is it specific to bone marrow-derived cells?

Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSCs) are intensively studied for regenerative medicine. Moreover, MSCs have paracrine effects, including immunomodulation that occurs through the secretion of soluble mediators, including nitric oxide or interleukin-6, transforming growth factor-beta, human leukocyte antigen G5, and prostaglandin E2. MSCs in the bone marrow are in close contact with T and B cells and regulate immunological memory by organizing defined numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. All of these biological effects are probably shared by all stromal cells, including fibroblasts and stem cells isolated from exfoliated deciduous teeth. The therapeutical implications are discussed.

in other clinical applications based on their capacity to limit scar formation through anti-fi brotic properties, to prevent apoptosis, to stimulate endogenous cells for regeneration, and to suppress the host immune response [4]. Such an immunosuppressive eff ect has been shown to occur mainly through the secretion of soluble factors by MSCs. Among the possible mediators identifi ed, indoleamine 2,3-dioxygenase (IDO), inducible nitric oxide synthase, and heme oxygenase-1 as well as the secretion of human leukocyte antigen G, transforming growth factor-beta, interleukin (IL)-6 or prostaglandin E 2 have been postulated to play a role, but the cells need to be licensed through interferon-gamma [5,6]. Th ese mecha nisms result in the inhibition of the proliferation of CD4 + and CD8 + T cells, B lymphocytes, and natural killer cells that have been shown mainly in vitro but also in vivo in a number of experimental models. MSCs have also been shown to induce in vivo regulatory T (Treg) cells through release of sHLAG5 and it has been shown that these foxP3 cells were functional. All of these biological eff ects are probably shared by all stromal cells, and similar dates have been shown with fi broblast (CJ, unpublished data). In the previous issue of Stem Cell Research & Th erapy, Yamaza and colleagues [1] demonstrate similar immunomodulatory activities of stem cells from human exfoliated deciduous teeth.

What is the role of mesenchymal stromal cells in physiology?
MSCs in the bone marrow are in close contact with T and B cells. MSCs regulate immunological memory by organizing defi ned numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. A distinct subpopulation of MSCs is characterized by the expression of CXCL12 and vCAM1. A distinct population of MSCs that express platelet-derived growth factor receptor-alpha with distinct properties is also described. Th eir high expression of CXCL12 and their developmental stability suggest that they might be the MSCs that

Abstract
Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSCs) are intensively studied for regenerative medicine. Moreover, MSCs have paracrine eff ects, including immunomodulation that occurs through the secretion of soluble mediators, including nitric oxide or interleukin-6, transforming growth factor-beta, human leukocyte antigen G5, and prostaglandin E 2 . MSCs in the bone marrow are in close contact with T and B cells and regulate immunological memory by organizing defi ned numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. All of these biological eff ects are probably shared by all stromal cells, including fi broblasts and stem cells isolated from exfoliated deciduous teeth. The therapeutical implications are discussed.

© 2010 BioMed Central Ltd
Mesenchymal stem cells immunosuppressive properties: is it specifi c to bone marrow-derived cells? provide a survival niche for memory plasma cells [7]. In contrast, another fraction of CXCL12 − vCAM1 + bone marrow MSCs expresses IL-7. Th ese cells are in close contact with memory CD4 + T cells and keep the T cells quiescent through the eff ect of IL-7 [8]. Th ese results suggest heterogeneity of MSCs in terms of immune and hematopoietic functions but also suggest that MSCs have a key role to maintain immune homeostasis.

Applications to immune diseases
Th e immunosuppressive capacities of MSCs have been evaluated in experimental autoimmune models, as well as in humans, to prevent acute graft-versus-host disease [9]. Zappia and colleagues [10] were among the fi rst to report the therapeutic effi cacy of MSCs in the experimental autoimmune encephalomyelitis murine model of multiple sclerosis. In this model, MSCs decreased the clinical signs associated with demyelinization when injected before or at disease onset. No therapeutic eff ect was observed when the injection occurred after disease stabili zation. Th e same results were observed in a model of autoimmune diabetes, in which MSC injection induced a decrease in mesangial thickening and in macro phage infi ltration, resulting in the prevention of pancreatic injury. In the experimental collagen-induced arthritis (CIA) model, diff erent studies have shown contrasted results on the role of MSCs. Th e fi rst study on the use of MSCs in CIA showed that the allogeneic C3H10T1/2 cells did not exert a benefi cial eff ect on CIA [4]. Since then, it has been reported that a single injection of primary MSCs prevented the occurrence of severe arthritis and was associated with a decrease in serum pro-infl ammatory cytokines and an increase in Treg cells [11]. Similar results have been obtained in vitro and in vivo with human adipose-derived stem cells that were shown to suppress T-cell response through the generation/activation of antigen-specifi c Treg cells. Th e role of MSCs in the immune-pathogeny of autoimmune diseases and the therapeutical perspective are expected in the near future, but the optimal source of stromal cells remains to be defi ned.