Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells

Abstract

In recent years, a large number of studies have contributed to our understanding of the immunomodulatory mechanisms used by multipotent mesenchymal stem cells (MSCs). Initially isolated from the bone marrow (BM), MSCs have been found in many tissues but the strong immunomodulatory properties are best studied in BM MSCs. The immunomodulatory effects of BM MSCs are wide, extending to T lymphocytes and dendritic cells, and are therapeutically useful for treatment of immune-related diseases including graft-versus-host disease as well as possibly autoimmune diseases. However, BM MSCs are very rare cells and require an invasive procedure for procurement. Recently, MSCs have also been found in fetal-stage embryo-proper and extra-embryonic tissues, and these human fetal MSCs (F-MSCs) have a higher proliferative profile, and are capable of multilineage differentiation as well as exert strong immunomodulatory effects. As such, these F-MSCs can be viewed as alternative sources of MSCs. We review here the current understanding of the mechanisms behind the immunomodulatory properties of BM MSCs and F-MSCs. An increase in our understanding of MSC suppressor mechanisms will offer insights for prevalent clinical use of these versatile adult stem cells in the near future.

EphB and ephrin-B interactions mediate human mesenchymal stem cell suppression of activated T-cells

“…Our data are consistent with the findings of Kawano et al, which stimulated murine T-cells with ephrin-B2 [35]. While MSC have been demonstrated to suppress T-cell proliferation by reducing IFN-g and IL-17 production [2,55,63], our study contributes to the current understanding, demonstrating that TNF-a and IL-2 may also play an important role during this process. It is known that Eph/ephrin interactions trigger numerous signaling pathways to mediate cellular functions such as cell attachment, migration, proliferation, and differentiation [14,19,21,64].…”

“…Previous studies have demonstrated that MSC, on being stimulated by IFN-c produced by activated T-cells, secrete soluble factors that play important roles in mediating MSC immunosuppressive properties such as IDO, TGF-b1, and NO [1,2,40]. In the present study, gene expression analyses were performed on MSC after incubation with or without IFN-g in the presence of EphB4-Fc, ephrin-B1-Fc, or human-Fc control.…”

“…A number of studies have reported that soluble factors secreted by MSC, such as TGF-b1, IDO, NO, HGF, PGE 2 and IL-10, play important roles in immunosuppressive effects [1,2,40,55,59]. In the present study, we showed, for the first time, that IDO expression was induced by MSC after stimulation with EphB4-Fc or ephrin-B1-Fc in the presence of IFN-g [37]; whereas TGF-b1 and iNOS expression was up-regulated after stimulation with EphB4-Fc alone.…”

“…As a result, MSC are unable to trigger T-cell activation but rather act as a third-party population to inhibit allostimulated T-cell proliferation [1,3]. These immunosuppressive properties have been reported to be mediated by different soluble factors such as hepatocyte growth factor (HGF), prostaglandin E2 (PGE 2 ), transforming growth factor-b1 (TGF-b1), indoleamine 2,3-dioxygenase (IDO), interleukin-10 (IL-10), nitric oxide (NO), and the contact-dependent B7-H1/PD-1 pathway [1,2,9,10]. While some of these factors partially contribute to the immunomodulatory properties of MSC, the exact underlying mechanisms that regulate MSC-mediated immune cell action remain to be elucidated.…”

“…ultipotential human bone marrow-derived mesenchymal stromal/stem cells (MSC) exhibit immunomodulatory properties that are capable of restraining allogeneic reactions [1][2][3] due to lack of expression of MHC class II antigens and co-stimulatory molecules such as CD40, CD80, CD86, or CD40L [4][5][6][7][8]. As a result, MSC are unable to trigger T-cell activation but rather act as a third-party population to inhibit allostimulated T-cell proliferation [1,3].…”