Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells

Abstract

IntroductionMultipotent human mesenchymal stromal cells (MSCs) are plasticadherent cells with triangular and fibroblastoid morphologic features, which have the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes. Furthermore, they express the cell-surface markers CD73, CD90, and CD105, while being negative for CD34, CD45, and human leukocyte antigen (HLA-DR). 1 Various tissues including bone marrow, fat, umbilical cord blood, or fetal tissues have been used as sources for MSCs. 2 Not only are MSCs immunoprivileged because they are poorly lysed by T cells, but they also have strong immunosuppressive effects. [3][4][5][6] Therefore, MSCs are of clinical interest for both regenerative medicine and immune suppression. MSCs have been used successfully for treatment of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. 7 In addition, data from mouse models for rheumatoid arthritis or multiple sclerosis suggest that MSCs may be effective in the treatment of autoimmune diseases. 8 In vitro studies have analyzed the immunomodulatory effects of MSCs in detail and showed that MSCs inhibit the proliferation of T cells independent of the T-cell stimulus (ie, the suppression was observed when T cells were activated by alloantigens, mitogens, or through T-cell receptor engagement by anti-CD3 in combination with anti-CD28 antibodies). [4][5][6] Moreover, the inhibition is MHC independent. 9,10 MSCs do not only inhibit T-cell proliferation directly, but also impair dendritic cell function (ie, MSCs interfere with dentritic cell [DC] differentiation, maturation, and activation), which is shown by compromised antigen presentation and altered cytokine release. [11][12][13][14] MSCs also suppress the proliferation of NK cells and modulate the functions of B cells. 2 Most studies agree in that no cell-cell contact is required for the MSC-mediated immunosuppressive effects. 15 Instead, soluble molecules are thought to mediate this inhibition. Possible candidate molecules include transforming growth factor-␤ (TGF␤), hepatocyte growth factor, 5 indoleamine-2,3-dioxygenase (IDO), 16 prostaglandin E2 (PGE2), 11,17,18 insulin-like growth factorbinding proteins, 19 heme oxygenase-1 (HO), 20 and HLA-G5. 21 Moreover, the mechanism of the suppressive effects may be species dependent, as some molecules were described to be involved in suppressive effects of mouse MSCs such as nitric oxide (NO). 22 Another novel candidate molecule recently described to be involved in suppressive effects of mouse MSCs is the MSC-derived CC chemokine ligand CCL2; the proteolytically processed form of CCL2 modulates immunoglobulin production by plasma cells and is involved in the beneficial effects of MSCs in experimental autoimmune encephalomyelitis. 23,24 However, blocking any single one of these molecules did not completely abrogate the immuno suppressive functions of MSCs, indicating that several signaling pathways are involved and some important mediators may have not been identified yet. Several a...

Stromal cells–are they really useful for GVHD?

“…Some of these factors are constitutively produced by MSCs, such as HLA-G5, 49 prostaglandin E 2 (PGE 2 ), 50 and galectins. 51 The immunomodulatory effects exerted by MSCs can be augmented if the cells are activated by cytokines such as IFN-g. [52][53][54] It has also been shown that MSCs can be activated by stimulation of their Toll-like receptors. 55 Another important mediator of suppression by stromal cells is the T-cell inhibitory enzyme indoleamine-2,3-dioxygenase (IDO).…”

How stem cells speak with host immune cells in inflammatory brain diseases

“…Data in Table 1 are in part summarized in (Chamberlain et al, 2008;Hall et al, 2006;Martino and Pluchino 2006;Pluchino et al, 2009b;Rojewski et al, 2008;Uccelli et al, 2008;Yuan et al, 2011). (Cusimano et al, 2012;Jaderstad et al, 2010) aracrine IDO-kynurenine MSCs (h) T cells, DCs T cell apoptosis, inhibition of antigen presentation (Lanz et al, 2010;Matysiak et al, 2008Matysiak et al, , 2011Meisel et al, 2004;Plumas et al, 2005 Bonnamain et al, 2012;Chabannes et al, 2007;Moll et al, 2011) Paracrine VEGF NPCs Microglia/macrophages Inhibition of microglial activation, proliferation and phagocytosis (Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine LIF NPCs Th17 cells Inhibition of Th17 cell differentiation (Cao et al, 2011;Horie et al, 2011;Kim et al, 2009a;Mosher et al, 2012) Paracrine Galectins MSCs/NPCs T cells Inhibition of T cell proliferation (Gieseke et al, 2010;Sioud 2011;Yamane et al, 2010Yamane et al, , 2011 Endocrine/Paracrine TSG-6 MSCs Macrophages Inhibition of macrophage activation, proliferation and phagocytosis (Fisher-Shoval et al, 2012;Lee et al, 2009;Roddy et al, 2011) EVs miR transfer MSCs/NPCs Multiple Post-transcriptional regulation (Bruno et al, 2009;Chen et al, 2010;…”

Mesenchymal Stromal Cells Mitigate Experimental Colitis via Insulin-like Growth Factor Binding Protein 7-mediated Immunosuppression

“…Other factors believed to mediate the immunomodulatory effect of MSCs, such as galectin-1, are constitutively expressed at a high level. 17 We speculated that the factors involved and the underlying mechanisms differed based on the type of tissue, disease microenvironments and the species. In order to promote the clinical application of MSCs in CD, it is therefore necessary to identify the MSC-driven immunomodulators and related mechanisms that function in the CD microenvironment.…”

“…17,27 Therefore, we analyzed the possible role of MSCderived IGFBP7 in suppressing the tumor necrosis factor (TNF)-α and IFN-γ expression in T-cells. Expectedly, MSC con significantly inhibited the expression of proinflammatory cytokines by activated T-cells.…”

“…16) and the galectins. 17 However, blockage of any one of these molecules is insufficient to abolish completely the immunoregulatory functions of MSCs, indicating that several other important mediators may have not been identified yet. Gieseke et al found that human MSCs exerted immunomodulatory functions in the absence of interferon (IFN)-γ receptor 1 signaling and IDO, and that this process might involve insulin-like growth factor binding proteins (IGFBPs).…”