Figure 7 Effects of immune cell activation state on mesenchymal stem cell immune-modulation. The differentiation state of immune cells can render them susceptible or refractory to mesenchymal stem cell (MSC) action. Though MSCs efficiently inhibit the activation … NK cells are generally in a resting state, but upon IL-2 activation, proliferate Everolimus RAD001 and differentiate into activated cytolytic and cytokine-producing cells capable of efficient lysis of target cells. MSCs robustly prevented resting NK cell activation and proliferation, but were only partially capable

of suppressing this process on NK cells that have been pre-exposed to IL-2[38]. Moreover, the extent of MSC suppression of NK cell proliferation in the latter case was ratio dependent, with decreasing suppression with increasing NK:MSC ratio. IL-2-pre-exposed, but not resting, NK cells also efficiently lysed autologous and allogeneic MSCs, and exhibited increased IFNγ production with MSC co-culture. Interestingly, IFNγ-pre-exposed MSCs had a better capacity of inhibiting pre-activated NK cell activity, presumably due to increased MHC-I expression on MSCs in response to inflammatory cytokine signaling, which negatively affects NK cell function. Under the arm of adaptive immunity, MSCs have been extensively shown to suppress

TH17 and Tc17 development, but less work has addressed MSC effects on memory T cells. Hsu and colleagues showed that MSCs specifically enhanced IL-17 expression in CD4+CD45RO+ memory T cells, but not in any other populations of CD4+ or CD8+ T cells[81]. These TH17 subsequently enhanced neutrophil function. It is thought that, since these memory T cells rapidly react to a pathogen challenge in vivo, they could interact with MSCs at peripheral sites to enhance their function and increase the T cell response for efficient pathogen elimination. Thus immune cell activation state is an important factor in influencing outcome with MSC interactions. THERAPEUTIC CONSIDERATIONS AND CONCLUSION Initial pre-clinical animal models of inflammatory conditions suggested that MSCs exerted a beneficial effect for

a range Carfilzomib of diseases and ushered in their potential use in controlling human diseases, especially autoimmune disease (Table ​(Table1).1). However, additional studies also indicate an exacerbation of disease symptoms, thus raising points to consider regarding the safe use of these cells in humans[82,83]. Importantly, MSCs represent a highly heterogeneous and pleiotropic population of stem cells. The intrinsic variability in the cellular make-up may influence multiple properties of how MSCs affect immune cell function and disease. Therefore, an intensified focus on further characterizing the subtypes of MSCs is desperately needed. The heterogeneity in the isolation, culturing, and expansion of MSC populations are known to affect the phenotype of MSCs[84].