[23, 25] Recently, Crop et al.,[26] reported the lysis of human MSC by NK cells, highlighting the need for better understanding of this interaction ahead of the clinical application of MSC. The non-specific inhibitory effects of MSC has also been observed on the in vitro differentiation of naive CD4+ T cells into T helper type 17 (Th17) cells as well on their production of IL-17, IL-22, IFN-γ and TNF-α.[22] Also, the function of T cells expressing T-cell receptor-γδ is impaired by MSC.[21] A number

of mechanisms have been implicated GS-1101 datasheet in MSC-mediated immunomodulation (Fig. 1). There is now consensus that the secretion of soluble factors is fundamental in MSC activity. Some soluble factors are constitutively secreted by MSC whereas others are induced when MSC are exposed

to specific inflammatory environments. It is unlikely that a single molecule is responsible for the effect, because the selective inactivation of only one is not sufficient to turn the immunosuppressive activity off. Furthermore, there are differences among species, at least between mouse and humans. In human MSC one of the most prominent mechanism is the one mediated by indoleamine 2-3-dioxygenase, which depletes the cellular microenvironment of the essential amino acid tryptophan, required for T-cell proliferation.[27] In contrast, murine MSC deliver their inhibitory activity especially Ensartinib supplier via inducible nitric oxide synthase (iNOS) while rat MSC use preferentially haem-oxygenase 1. However, other molecules have been clearly demonstrated to be involved and they comprise transforming growth factor-β1, hepatocyte growth factor, prostaglandin E2 and soluble HLA-G.[28, 29] The most recent report based on gene expression profiling of human MSC, has revealed that galectin-1, highly expressed intracellularly

and at the cell surface of MSC, is released in a soluble form and mediates immunosuppression. Amobarbital A stable knockdown of galectin-1 resulted in a significant reduction of the immunomodulatory properties on T cells but not on non-alloreactive NK cells.[30] The reasons for such selectivity have not been clarified. In the presence of an inflammatory environment containing IFN-γ, TNF-α and IL-1β, MSC produce high levels of the chemokines CXCL-9 and CXCL-10 in response to which T cells migrate to the vicinity of MSC, where high levels of iNOS favour the inhibition of T cells. Acting either separately or in combination, pro-inflammatory cytokines drive the up-regulation of ICAM-1, VCAM-1, HLA class I and class II molecules and the inhibitor ligand B7-H1 and these might further potentiate MSC function.[31] The notion that most effector mechanisms are exerted by the secretion of soluble factors has led to testing the possibility of re-creating an immunomodulatory niche by using MSC-conditioned medium.