Moïra François

The discovery of the immunosuppressive properties of mesenchymal stromal cells (MSCs) has given new hope to patients suffering from autoimmune diseases as their lack of immunogenicity in addition to their immunosuppressive and regenerative properties makes them an ideal biological agent for the treatment of various disorders ranging from autoimmune diseases to tissue injury. The translational promises of a safer and more effective therapy has however suffered a setback with the recent release of the results from Phase III randomized clinical trial using MSCs for treatment of steroid refractory acute graft‐versus‐host disease (GvHD), which failed to meet its primary efficacy endpoint. In this review, we will address the current knowledge of the immunosuppressive mechanisms of MSCs from in vitro studies to animal models and then look upon the results obtained from human clinical trials in order to provide failure analysis of negative studies. We will conclude by proposing future directions which could help address this issue and allow rational development of MSCs as an effective and useful cell‐based immunotherapeutic. J. Cell. Physiol. 227: 3535–3538, 2012.

Bone-derived mesenchymal stem cells (MSCs) are important cells for use in cell therapy, tissue engineering, and regenerative medicine, but also to study bone development, homeostasis, and repair. However, little is known about their developmental ontology and in vivo identity. Because fibroblast growth factors (FGFs) play key roles in bone development and their receptors are developmentally regulated in bones, we hypothesized that MSCs should express FGF receptors (FGFRs), reflecting their developmental origin and potential. We show here that FGFR1/2 are expressed by rare mesenchymal progenitors in putative MSC niches in vivo, including the perichondrium, periosteum, and trabecular marrow. FGFR1+ cells often appeared as pericytes. These cells display a characteristic MSC phenotype in vitro when expanded with FGF-2, which appears to maintain MSC stemness by inhibiting cellular senescence through a PI3K/AKT-MDM2 pathway and by promoting proliferation. FGFRs may therefore be involved in MSC self-renewal. In summary, FGFR1/2 are developmentally regulated markers of MSCs in vivo and in vitro and are important in maintaining MSC stemness.

It is unknown whether mesenchymal stromal cells (MSC) can regulate immune responses targeting tumor autoantigens of low immunogenicity. We tested here whether immunization with MSC could break immune tolerance towards the ErbB-2/HER-2/neu tumor antigen and the effects of priming with IFN-γ and tumor necrosis factor-α (TNF-α) on this process. BALB/c– and C57BL/6-derived MSC were lentivirally transduced to express a kinase-inactive rat neu mutant (MSC/Neu). Immunization of BALB/c mice with nontreated or IFN-γ–primed allogeneic or syngeneic MSC/Neu induced similar levels of anti-neu antibody titers; however, only syngeneic MSC/Neu induced protective neu-specific CD8⁺ T cell responses. Compared to immunization with nontreated or IFN-γ–primed syngeneic MSC/Neu, the number of circulating neu-specific CD8⁺ T cells and titers of anti-neu antibodies were observed to be decreased after immunizations with IFN-γ– plus TNF-α–primed MSC/Neu. In addition, syngeneic MSC/Neu seemed more efficient than IFN-γ–primed MSC/Neu at inducing a protective therapeutic antitumor immune response resulting in the regression of transplanted neu-expressing mammary tumor cells. In vitro antigen-presenting cell assays performed with paraformaldehyde-fixed or live MSC showed that priming with IFN-γ plus TNF-α, compared to priming with IFN-γ alone, increased antigen presentation as well as the production of immunosuppressive factors. These data suggest that whereas MSC could effectively serve as antigen-presenting cells to induce immune responses aimed at tumor autoantigens, these functions are critically regulated by IFN-γ and TNF-α. Cancer Res; 70(20); 7742–7. ©2010 AACR.

Human mesenchymal stem cells (hMSCs) are being considered for clinical trials of multiple sclerosis (MS). We examined the effects of adult bone marrow‐derived hMSCs on responses of primary human Th1, Th17, and Th1/17 double‐expressing T‐cell subsets, all implicated in MS. As expected, soluble products from hMSCs inhibited Th1 responses; however, Th17 responses were increased. Secretion of interleukin (IL)‐10, considered anti‐inflammatory, was decreased. Pretreating hMSCs with the proinflammatory cytokine IL‐1β accentuated these effects, and caused decreases in the Th1/17 subset. These findings underscore the importance of further preclinical work and immune‐monitoring to define hMSC effects on disease‐relevant immune responses under variable conditions. ANN NEUROL 2010

Recent studies involving bone marrow mesenchymal stromal cells (MSCs) demonstrated that interferon (IFN)–γ stimulation induces major histocompatibility complex (MHC) class II–mediated antigen presentation in MSCs both in vitro and in vivo. Concordantly, we investigated the ability of MSCs to present extracellular antigen through their MHC class I molecules, a process known as cross-presentation. Using an in vitro antigen presentation assay, we demonstrated that murine MSCs can cross-present soluble ovalbumin (OVA) to naive CD8⁺ T cells from OT-I mice. Cross-presentation by MSC was proteasome dependent and partly dependent on transporter associated with antigen-processing molecules. Pretreatment of MSC with IFN-γ increased cross-presentation by up-regulating antigen processing and presentation. However, although the transcription of the transporter associated with antigen processing-1 molecules and the immunoproteasome subunit LMP2 induced by IFN-γ was inhibited by transforming growth factor-β, the overall cross-presentation capacity of MSCs remained unchanged after transforming growth factor-β treatment. These observations were validated in vivo by performing an immune reconstitution assay in β₂-microglobulin^−/− mice and show that OVA cross-presentation by MSCs induces the proliferation of naive OVA-specific CD8⁺ T cells. In conclusion, we demonstrate that MSCs can cross-present exogenous antigen and induce an effective CD8⁺ T-cell immune response, a property that could be exploited as a therapeutic cell-based immune biopharmaceutic for the treatment of cancer or infectious diseases.