The Immunoregulatory Mechanism Related Research Of Bone Marrow-derived Flk-1~+ Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs), in addition to their in vitro expansion and multilineage differentiation, have low immunogenicity and immunoregulatory properties. Thus, there are bright preventive or therapeutic perspectives in application of MSCs for the repair of tissue damage, treatment of autoimmune disease, induction of allogeneic transplantation tolerance, and so on. Due to their low expression of MHC-Ⅰantigens and no expression of MHC-Ⅱantigens and such costimulatory molecules as CD80, CD86 and CD40. MSCs possess low immunogenicity, escape immune surveillance, and therefore repair allogeneic tissue damage. Although MSCs do not express MHC antigens and costimulatory molecules at the time of in vitro culture, they are certain to express these antigens and molecules after they differentiate into committed cells during repairing allogeneic tissue damage in vivo. Why they can remain and no rejection happens in the host cannot be explained by their lack of immunogenicity. However, the mechanisms relevant to these phenomena have so far been poorly understood. Based on these questions, we preliminarily investigated MSCs on their immunogenic change principles and immunomodulatory mechanisms, and provided a new evidence for their further application.In part one of this study, we first used an in vitro osteogenic differentiation or interferon (IFN)-γpretreatment model, to simulate the microenvironment of differentiation or inflammation in vivo and explore the changes of immunological characteristics of MSCs and their relevant mechanisms in the osteogenesis or the presence of IFN-γ. The results showed that after 10 days of osteogenic differentiation or 48 hours of IFN-γpretreatment, MSCs still remained their low immunogenicity and more prominent immunoregulatory activity. In addition, we also detected a high level of expression of Jagged-1 molecules, and proved that the maintenance of their immunological characteristics was attributed to up-regulation of these molecules. So we propose that immunoregulatory activity of MSCs, to some extent depending on Jagged-1, might be stronger after multilineage differentiation or inflammatory factor influence, and further disclose a possible mechanism accounting for the reason that no rejection occurs after allogeneic MSCs differentiate into the committed cells in host (Model picture).Our previous research, that MSCs influence mature and differentiation of dendritic cells (DCs), has displayed a likely immunosuppressive mechanism by MSCs. However, whether they also affect the fate of mature DCs remains unknown. In part two, we therefore investigated the effect of MSCs on mature DCs, and demonstrated that MSCs could induce full mature DCs to differentiate into a new regulatory DC population in vitro, which had a low level of expression of Ia, but high CD11b expression and strongly inhibited the lymphocyte proliferation. Moreover, we also found a large-scale increase of Jagged-2 on the surface of these DCs, and proved that their immunological characteristics are dependent on Jagged-2. We thus speculate that MSCs might indirectly perform their immunomodulatory activity, because of their driving full mature DCs to differentiate into a new type of Jagged-2 dependent regulatory DC population and escape their apoptotic destiny after presenting antigens. Our results further indicate that there is another potential mechanism underlying the survival of the MSC-derived committed cells in allogeneic host (Model picture).