How Are Mesenchymal Stem Cells Related to Immunity (Part Three)
The immune regulation function of MSCs is affected by many factors in the inflammatory environment, and immunosuppressants are often used to treat diseases related to the immune system. This raises an important scientific question: Will immunosuppressants affect the immune regulation function of MSCs? Immunosuppressive treatments are similar to MSCs in that they all down-regulate the inflammatory response by suppressing effector T cells. Based on this, many studies have combined MSCs with commonly used immunosuppressants cyclosporine A or dexamethasone. Cyclosporine A can block T cell activation and is often used to treat organ transplant rejection or autoimmune diseases. MSCs can also induce tolerance in transplanted mice, but the combined use of cyclosporine A can reverse the therapeutic effect of MSCs. Similarly, dexamethasone, as another widely used immunosuppressive agent, has been found to reverse the immunosuppressive effect of MSCs in vivo and in vitro, which is related to the combination with dexamethasone blocks iNOS expression in human MSCs and the expression of IDO in human MSCs. Therefore, similar to TGF-β, immunosuppressants can also cause MSCs to lose their immunosuppressive function in an inflammatory environment. This finding is of great significance to guide the clinical application of MSCs.
MSCs are widely distributed in almost all tissues, and have powerful immunosuppressive functions in the inflammatory environment. So why can’t endogenous MSCs alleviate immune imbalances like exogenous MSCs? One reason could be that the immune regulatory function of MSCs is obtained during in vitro culture; another possible explanation is that the amount of MSCs cultured in vitro is generally 1 × 106 to 2 × 106 per mouse, and 1 per kilogram of human 1×106 to 2 ×106. This high-dose injection, coupled with the accumulation of MSCs to the injury site, enhances the function of MSCs injected in vitro. At present, although the lack of specific markers of MSCs has limited the understanding of the role of endogenous MSCs in immune regulation, however, in any case, the plasticity regulatory mechanism of exogenous infusion and the role of endogenous MSCs in immune regulation is fully clarified the rational application of MSCs and the formation of new models for their clinical application are of great significance.
Clinical Application of MSCs
Since MSCs successfully treated severe steroids and cyclosporine resistance to GVHD in 9-year-old boys in 2004, many animal experiments and clinical studies have suggested the broad application prospects of MSCs in the treatment of organ failure. Currently, more than 500 clinical trials registered in the NIH are related to MSCs. Many studies have shown that MSCs can significantly improve cardiovascular disease, liver disease, GVHD, and autoimmune diseases. During the course of treatment, the interaction of MSCs and inflammation plays a key role. Therefore, it has been suggested that immune regulation should be one of the standards for MSCs products. During the course of different diseases, the immune microenvironment of inflammatory tissues is constantly changing, which has different effects on MSCs, which determines the fate and therapeutic effect of infusion of MSCs to a certain extent.
The plasticity of MSCs immune regulation should be an important basis for its clinical application guidance. At the same time, the therapeutic effect can be improved by modifying its immune regulation function. Related clinical studies have found that MSCs are most effective against acute inflammatory diseases that are immunosuppressive. The first successful clinical application of MSCs is the infusion of allogeneic and haploid bone marrow-derived MSCs into cyclosporine and steroid-resistant Grade IV acute GVHD patients, and other drug-resistant inflammatory diseases such as systemic lupus erythematosus are examples of successful cures by MSCs. In this immunosuppressant-resistant patient, it is possible that persistent inflammation has stimulated the immunosuppressive function of MSCs. In contrast, in immunosuppressive patients, MSCs combined with cyclosporine or steroids have no therapeutic effect. These studies suggest that the immunosuppressive function of MSCs requires the induction of strong inflammatory factors, and low concentrations of inflammatory factors will make them play an immune promoting role. Therefore, the clinical efficacy of MSCs mainly depends on the levels of inflammatory factors they are exposed to. Therefore, pretreatment of MSCs with inflammatory factors before infusion can be used as a way to strengthen the immunosuppressive ability of MSCs. In animal models of enteritis or acute myocardial ischemic injury, this pretreatment does improve the therapeutic effect of MSCs. In addition, treatment with IFN-γ pretreated MSCs can significantly improve survival in GVHD mice. Similarly, IFN-γ and TNF pretreated MSCs are far more effective in treating concanavalin A-induced mouse hepatitis than non-pretreated cells, and the addition of IL-17 during pretreatment can further improve the efficacy. This pretreatment may mimic the inflammatory environment of the disease. The success of this treatment strategy also indicates that inflammation plays an important role in activating the immunosuppressive function of MSCs. Although most of these findings are in preclinical studies, comprehensive disclosure of the intrinsic mechanisms of MSCs plasticity in immune regulation will help to develop more new clinical treatment schemes based on MSCs.
A large number of data indicate that the inflammatory state determines the functional fate of MSCs. Because the activation of MSCs’ immunosuppressive function requires inflammation to reach a certain level, its therapeutic effect may not be attributed to differences in individual inflammation levels. In addition, clinically applied anti-inflammatory treatments may change the inflammatory factor profile in the tissue microenvironment, thereby affecting the efficacy of MSCs. Indeed, studies have found that the combination of MSCs and dexamethasone can cause MSCs to be ineffective in treating diseases, which is closely related to dexamethasone blocking MSCs expression of iNOS or IDO. In the liver fiber model, dexamethasone can reverse the immunosuppressive effect of MSCs, thereby completely eliminating the therapeutic effect of MSCs. These results suggest that MSCs should be avoided in combination with immunosuppressive agents when treating diseases.
Although the pathophysiology of MSCs has not been fully elucidated, a large number of animal experiments and clinical studies have demonstrated the potential of MSCs as a new strategy in the treatment of various diseases. With the discovery of the importance of appropriate inflammatory stimuli in the role of MSCs in immunosuppression, a systematic analysis of the mechanism of MSCs immune regulation and the optimization of MSCs formation plays an important role in more reasonable and effective clinical applications. In addition, in order to optimize the treatment of MSCs, the development of practical methods to detect the inflammatory status in patients during MSCs infusion, and the discovery of biomarkers that can predict the efficacy of MSCs are currently urgent problems to be solved.
Conclusion
In recent years, a large number of studies have revealed the role of MSCs in inflammation and tissue repair from a new perspective. In addition to the differentiation potential of MSCs, its immunoregulatory function has also given it the potential to be used in the treatment of immune-related diseases, and has attracted much attention. Although the relationship between the long-term colonization of MSCs at the injury site and its effect on disease treatment is not clear, exogenous MSCs can indeed be recruited to the injury site and participate in the regulation of the injury microenvironment. The tissue repairing ability of MSCs depends on strong inflammatory stimulus, which not only confers MSCs with immunosuppressive function, but also promotes the secretion of a large number of growth factors by MSCs. However, the inflammatory environment is not constant. MSCs can exert differential regulation on the immune response due to dynamic changes in conditions such as different inflammation levels or cytokine types and immunosuppressive agents. Therefore, it can be seen that the plasticity of the MSCs’ immune regulatory function is of great significance for clinical application. According to the specific inflammatory state, using the characteristics of MSCs immune regulation function to develop personalized clinical treatment strategies will comprehensively optimize MSCs-related clinical methods to achieve the optimal regulation of inflammatory response at different stages of disease progression.