Species Variation in the Mechanisms of Mesenchymal Stem Cell-Mediated Immunosuppression

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) hold great promise for treating immune disorders because of their immunoregulatory capacity, but the mechanism remains controversial. As we show here, the mechanism of MSC-mediated immunosuppression varies among different species. Immunosuppression by human-or monkey-derived MSCs is mediated by indoleamine 2,3-dioxygenase (IDO), whereas mouse MSCs utilize nitric oxide, under the same culture conditions. When the expression of IDO and inducible nitric oxide synthase (iNOS) were examined in human and mouse MSCs after stimulation with their respective inflammatory cytokines, we found that human MSCs expressed extremely high levels of IDO, and very low levels of iNOS, whereas mouse MSCs expressed abundant iNOS and very little IDO. Immunosuppression by human MSCs was not intrinsic, but was induced by inflammatory cytokines and was chemokine-dependent, as it is in mouse. These findings provide critical information about the immunosuppression of MSCs and for better application of MSCs in treating immune disorders.

Mesenchymal Stem Cell Therapy Promotes Corneal Allograft Survival in Rats by Local and Systemic Immunomodulation

“…That is, pretreatment of MSCs with a cocktail of pro-inflammatory cytokines (predominantly a combination of one or more of IFN-g, TNF-a and IL-1b) has been shown to activate or ''license'' the cells, thereby increasing their production of immunosuppressive molecules such as indoleamine 2,3-dioxygenase (IDO) in the case of human MSCs and inducible nitric oxide synthase (iNOS) in the case of mouse MSCs in vitro and in vivo and, as a result, increasing their therapeutic potential (25)(26)(27)(28)(29)(30). Although this concept was investigated in this study, IFN-gtreated syn-MSCs were as ineffective at prolonging allograft survival as untreated syn-MSCs ( Figure 1A).…”

Stromal cells–are they really useful for GVHD?

“…54 This demonstrates the variation among different species regarding the mechanisms of immune suppression by MSCs and the translational difficulties that might occur when validating a new MSC therapy in animal models. 66 MSCs may need to be licensed by IFN-g or nitric oxide, or transduced with IL-10 to ameliorate GVHD and improve survival in mouse models. 31,54,67 STROMAL CELL-DERIVED EXOSOMES AND MICROVESICLES Exosomes and microvesicles are small but complex entities that contain both immunomodulatory proteins and microRNA, and have homing abilities.…”

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

“…It is critical to define mediators associated with immunomodulation for all animal species individually, as it is clear that there are strong inter-species differences in MSCs responses to activation. For example, rodent MSCs and human MSCs differ slightly in their modulatory potential and mediators [26].…”

“…Human MSCs express the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), known to suppress T-cell responses [4,5,26]. IDO has been implicated in the induction of tolerogenic DCs, the switch to a Th2-dominant cytokine inflammatory response and the induction of Tregs.…”