Advancement of Mesenchymal Stem Cell Therapy in Solid Organ Transplantation (MISOT)

Abstract

There is evolving interest in the use of mesenchymal stem cells (MSC) in solid organ transplantation. Pre-clinical transplantation models show efficacy of MSC in prolonging graft survival and a number of clinical studies are planned or underway. At a recent meeting of the MISOT consortium (MSC In Solid Organ Transplantation) the advances of these studies were evaluated and mechanisms underlying the potential effects of MSC discussed. Continued discussion is required for definition of safety and eventually efficacy endpoints for MSC therapy in solid organ transplantation.

On the 17th and 18th of January 2010, the second meeting on the use of mesenchymal stem cells in solid organ transplantation (MISOT) took place in Rotterdam, the Netherlands. The focus of this meeting was to evaluate the progression of mesenchymal stem-cell (MSC) therapy in clinical organ transplantation. A number of protocols for planned and recently started clinical studies in kidney and liver transplantation were presented. First, these studies were build on the presumed immunosuppressive and regenerative potential of MSC (^{1, 2}) and second on the beneficial effect of MSC therapy in other applications, in particular for the treatment of graft-versus-host disease (³), and also for healing of tissue toxicity and hemorrhages (⁴).

The immunosuppressive effects of MSC include inhibition of T-cell proliferation, inhibition of dendritic cell maturation, and induction of regulatory T cells. The regenerative effects of MSC were initially attributed to their multilineage differentiation capacity, but more recently the idea that MSC secrete growth factors that induce proliferation and differentiation of more committed progenitor cells has gained popularity. In combination with their proposed low immunogenicity, MSC seem to be the ideal candidates for cell therapy. However, translation of the beneficial capacities of MSC into successful application in clinical organ transplantation is complex. The properties of MSC in culture may be different from those of their in situ and infused counterparts. The immunophenotype of culture expanded MSC for instance, generally used to characterize MSC, may not be a property of the in vivo progenitor but in practice be an immunophenotype of plastic adherent MSC. MSC cultured under nonadherent conditions express a different set of surface markers and coagulate in spheroids, which promotes cell–cell interactions and might represent a more comparable condition to the in situ situation (⁵).

The perhaps atypical characteristics of MSC in culture do not necessarily imply that these properties are disadvantageous for the use of MSC in organ transplantation. In vitro preparation of MSC offers the possibility to control the characteristics of MSC. One option is to culture MSC in the presence of proinflammatory cytokines that enhance the immunosuppressive effect of MSC. It has been demonstrated that MSC precultured with interferon-γ have increased production of proangiogenic and antiinflammatory cytokines when compared with conventional MSC and, as a result, can be administered at severalfold lower doses with equivalent efficacy (⁶). Furthermore, MSC secrete factors into the culture medium that have immunosuppressive effects and promote liver and kidney regeneration (^7–9). Culturing of MSC under serum-free conditions has the potential benefit of generating MSC-conditioned medium that could have therapeutic value in organ transplantation. This is worth further exploration.

However, the secretion of growth factors only cannot explain in full the in vivo effects of MSC observed in animal models. Apart from the fact that MSC seem to disappear shortly after infusion and have little time to secrete immunomodulatory and tissue repair factors, a number of studies show different effects of syngeneic and allogeneic MSC in transplantation models (^{10, 11}). Currently, studies indicate that MSC that share major histocompatibility complex antigens with a donor graft have superior capacity of inducing long-term tolerance. It is possible that one of the effects of donor MSC in a transplantation setting is desensitization against donor antigens. Nevertheless, syngeneic MSC are effective in some animal models, indicating that other mechanisms must be in place too. One of the challenges for MSC research is to prove whether the effects of MSC infusion are really based on an active response of MSC, consisting of the secretion of immunomodulatory and regeneration factors or perhaps the differentiation of MSC into functional cell types, or whether MSC play a passive role. Such passive effects of MSC could include triggering of the immune system by human leukocyte antigen mismatches between MSC and recipient, or triggering of clean up procedures after the accumulation of MSC in the lungs. More knowledge of the mechanisms of immunomodulation and tissue regeneration by infused MSC is crucial for the design of clinical trials.

It is clear that more basic research is needed to understand how MSC can most effectively be applied in organ transplantation. Well-controlled clinical trials can greatly accelerate the process. Early safety trials should take the opportunity to look at mechanistic effects of MSC in clinical organ transplantation accompanied by proper biomarker evaluation. Several phase I trials testing the safety of MSC infusion before and after liver and kidney transplantation are currently in preparation (University Medical Center Regensburg, Germany; Erasmus Medical Center, Rotterdam, the Netherlands; Free University Brussels, Belgium; University Medical Center Hamburg-Eppendorf, Germany) and a small number have recently started (Ospedali Riuniti-Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Leiden University Medical Center, the Netherlands). Very preliminary results indicate that MSC therapy in transplantation patients is feasible and safe. Hopefully, new data from the first trials will confirm this, while ongoing preclinical studies can further address the effect of MSC cell source, activation state, and identify their optimal efficacy (¹²).

Continued discussion is required for clear definition of safety endpoints in early phase I studies, which is complicated by surgical procedures and perturbation in many organ systems, particularly in liver transplantation. Infusional toxicity linked to pulmonary complications or immune hyper-reactivity may be clear endpoints, but with other organ endpoints it would be difficult to attribute product-related serious adverse effects (SAE). Furthermore, the dialogue on the implementation of MSC therapy in organ transplantation should continue. Because of the complex nature of organ transplantation, with its immune and tissue injury components, there are multiple motives and approaches for MSC therapy. Perhaps the most apparent objective for MSC therapy is to limit chronic allograft injury by sparing long-term antirejection drugs and eventually promoting tolerance. However, MSC therapy has the potential for far wider applications in organ transplantation, from stretching the life-span of progressively deteriorating organs and delay transplantation to preservation of procured organs, reduction and repair of ischemia-reperfusion injury, and treatment of acute rejection. For most of these applications, it is crucial to apply MSC with optimal concurrent immunosuppressive regimen to support but not surpass the immunomodulatory and regenerative effects of MSC. Further studies are needed to get additional insight in the most advantageous drug combinations and timing of their administration in respect to MSC infusion in clinical transplantation.

Progress with the application of MSC in organ transplantation can be made when basic research is combined with well-designed clinical studies. MISOT is a platform at which these studies can be discussed and tuned. Undoubtedly, the road to application of MSC in organ transplantation will not be without hurdles. However, these hurdles should encourage adaptation and optimization of MSC therapy. The coming years will be critical for the implementation of the learned lessons from basic and clinical studies in MSC therapy in solid organ transplantation.

ACKNOWLEDGMENT

The authors thank the International Liver Transplantation Society for supporting the 2nd MISOT meeting.