Mesenchymal stem cells in arthritis: role of bone marrow microenvironment

Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSCs) are intensively studied for regenerative medicine. Moreover, MSCs are potent immunomodulatory cells that occur through the secretion of soluble mediators including nitric oxide, transforming growth factor beta, and HLAG5. The MSCs, however, are also able to express inflammatory mediators such as prostaglandin E2 or IL-6. MSCs in the bone marrow are in close contact with T cells and B cells, and they regulate immunological memory by organizing defined numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. The role of MSCs in arthritis remains controversial - in some studies, murine allogeneic MSCs are able to decrease arthritis; in other studies, MSCs worsen the local inflammation. A recent paper in Arthritis Research and Therapy shows that bone marrow MSCs have decreased osteoblastic potential in rheumatoid arthritis, which may be related to chronic inflammation or to loss of expression of IL-1 receptor agonist. That article raises the importance of the bone marrow microenvironment for MSC biology.


Mesenchymal stem cells are present in the arthritic joint
MSCs are defi ned according to three criteria: their property to adhere to plastic, their phenotype (CD73 + , CD90 + , CD105 + , CD45 -, CD14 -, CD11b -, CD34 -) and their capacity to diff erentiate into three lineages: chondro cytes, osteoblasts and adipocytes [2]. Besides these factors, MSCs display a broader diff erentiation potential. Th ey can diff erentiate into myocytes, tendinocytes, ligamento cytes, cardiomyocytes, and other cell types [3]. Th eir diff erentiation potential is largely dependent on environmental factors; in particular, specifi c growth factors -but, as an example, hypoxia and the threedimensional environment are also pivotal factors that probably help to support the chondrocytic phenotype. MSCs have been identifi ed in the bone marrow, but also in other tissues of the joint including adipose tissue, periosteum, peri chondrium, synovial tissue and cartilage [4][5][6][7].

Immunomodulatory eff ects of mesenchymal stem cells
In addition to their potential for tissue repair, MSCs are potent modulators of immune responses, having antiproliferative and anti-infl ammatory capacities. Although terminally diff erentiated stromal cells, such as fi broblasts, also share some immunosuppressive activities with MSCs, as shown by their ability to suppress in vitro T-cell proliferation [8], they do not exert in vivo the suppressive eff ect mediated by MSCs. MSC-mediated immunosuppression requires their previous activation by immune cells through proinfl ammatory cytokines IFNγ with TNFα or IL-1β [9]. Moreover, other molecules including indoleamine-2,3-dioxygenase, heme oxidase as well as HLAG5 have been involved in MSC-mediated immuno suppression.
MSCs, however, are also able to express infl ammatory mediators such as prostglandin E 2 or IL-6. Th e

Abstract
Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSCs) are intensively studied for regenerative medicine. Moreover, MSCs are potent immunomodulatory cells that occur through the secretion of soluble mediators including nitric oxide, transforming growth factor beta, and HLAG5. The MSCs, however, are also able to express infl ammatory mediators such as prostaglandin E 2 or IL-6. MSCs in the bone marrow are in close contact with T cells and B cells, and they regulate immunological memory by organizing defi ned numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. The role of MSCs in arthritis remains controversialin some studies, murine allogeneic MSCs are able to decrease arthritis; in other studies, MSCs worsen the local infl ammation. A recent paper in Arthritis Research and Therapy shows that bone marrow MSCs have decreased osteoblastic potential in rheumatoid arthritis, which may be related to chronic infl ammation or to loss of expression of IL-1 receptor agonist. That article raises the importance of the bone marrow microenvironment for MSC biology.

E D I TO R I A L
*Correspondence: christian.jorgensen@inserm.fr 1 Inserm, U844, Montpellier F-34091, France Full list of author information is available at the end of the article production of this enzymatic product of arachidonic acid metabolism is enhanced in MSCs upon TNFα or IFNγ stimulation. Th is may explain why in a particular infl ammatory environment MSCs may have a paradoxal eff ect on immune cells. In the bone marrow niche, another example of the role of MSCs is the production of receptor activator for NF-κB ligand (RankL) and of osteoprotegerin, which will stimulate osteoclast formation from hematopoietic precursor cells and will inhibit bone formation, respectively. Moreover, 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, characterized by the expression of CXCL12 and vascular cell adhesion molecule-1, might provide a survival niche for memory plasma cells [10]. In contrast, another fraction of CXCL12-negative 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. Th ese results suggest heterogeneity of MSCs in terms of immune and hematopoietic functions, but also suggest that MSCs play a key role to maintain immune homeostasis.

Mesenchymal stem cells and autoimmunity
In rheumatoid arthritis, using the experimental collageninduced arthritis model, contrasting results are reported. A single injection of MSCs was shown to prevent the occurrence of severe arthritis, which was associated with a decrease in serum proinfl ammatory cytokines [11]. We have shown that the allogeneic C3H10T1/2 MSC line did not exert a benefi cial eff ect on collagen-induced arthritis [12]. As in other autoimmune models, MSCs were not observed in the target organ. Zappia and collaborators reported the therapeutic effi cacy of MSCs in the experimental auto immune encephalomyelitis murine model of multiple sclerosis [13]. In this model, MSCs decreased the clinical signs associated with demyelini zation when injected before or at the onset of disease. Th e same results were observed in a model of autoimmune diabetes, where MSC injection induced a decrease in mesangial thickening and in macrophage infi ltration, resulting in the prevention of pancreatic injury [14].
Stromal cells are no longer second citizens but are fi rstline players. Th ey appear as major regulatory cells in skeletal tissues controlling infl ammation, immune response, fi brosis and tissue regeneration. A better understanding of the interactions between stromal cells and immune cells is required for therapeutic applications and to validate the strong potential of MSCs in rheumatologic diseases. Th e work presented by Mohanty and colleagues underlines the link between osteoporosis, infl ammation and MSCs. Th e in vivo behavior of MSCs in the context of pathological situations remains to be further studied in rheumatoid arthritis. Abbreviations IFN, interferon; IL, interleukin; MSC, mesenchymal stromal cell; NF, nuclear factor; TNF, tumor necrosis factor.