Few medical advancements have captivated public interest as much as stem cell therapies. In fact, one of the original stem cell therapies was described in this very journal nearly 50 years ago1,2: the mesenchymal stem cell. Now known as mesenchymal stromal cells (MSCs),3 a more appropriate name due to their limited capacity to differentiate into somatic cell types, clinical evidence for their potential benefits is steadily mounting.
The current nomenclature change reflects 2 important clinical advantages for MSC therapy in comparison to bona fide stem cells: no risk of teratoma formation and fewer ethical concerns related to isolation and expansion methods. Moreover, the ease in isolation and expansion makes MSC therapy economically attractive. These advantages coupled with credible immunosuppressive effects experimentally have led to much interest in their use in solid organ,4 cellular,5 and vascularized composite transplantation6,7 as well as other immune-mediated pathologies,8 and a rush toward clinical trials. Although there is some evidence that these cells have therapeutic effects through their regenerative properties,9-11 it is principally their broad immunosuppressive activity, and perhaps induction of regulatory T cells,12 that is of interest.
The first clinical studies of MSC therapy were reported over a decade ago and hundreds of trials continue to be registered in European and North American databases. However, very little is understood regarding the clinical efficacy of these cells in transplantation. The paucity of evidence is striking given the widespread commercialization and availability of MSC therapy in many countries. The summary of the current state of the art of MSC therapy in renal transplantation from Reinders and colleagues13 is therefore timely and welcome.
When investigating the field, the lack of consistency in cell description and the variety of isolation techniques mean that comparisons between studies are impossible. However, the International Society for Cellular Therapy’s position statement14 has provided much needed clarity. Their definition requires 3 components for defining MSCs: adherence to plastic, specific surface antigen expression, and the ability to differentiate into osteoblasts, adipocytes, and chondrocytes in vitro. Naturally, these are minimum requirements, and additional clinical release criteria will be required in different countries. Helpfully, the description provided in the review in this issue of Transplantation provides useful information regarding the types of MSCs used in ongoing trials in renal transplantation.
MSCs may be derived from several sources, with each source exhibiting specific immunological properties.15 The most commonly used sources in reported clinical trials are bone marrow and adipose tissue. Reinders and colleagues16 summarized 7 published trials in renal transplantation with a total of 141 patients treated with MSCs derived from bone marrow. In these limited studies, there are hints of improved outcomes with reduced requirements for drug immunosuppression as well as enhanced renal function. However, the difficulty in defining useful short-term endpoints in renal transplantation clinical trials limits the ability to understand the true efficacy of MSC therapy. More concerning is the evidence of an increase in the incidence of opportunistic infections which was reported in a study from the same group in Leiden. This is not unexpected given that MSCs exert immunosuppressive effects that are nonspecific and not regulated or directed in the same manner as a leukocyte. Ostensibly, this broad activity raises some doubts regarding the overall benefits of MSC therapy versus traditional immunosuppression.17
There remain many questions regarding the specific techniques of clinical application as well as the practicalities of Good Manufacturing Practice manufacture, an issue which is examined by Reinders et al. A discussion of these issues is crucial given the lack of consistency and anecdotal nature of many clinical trials. At this juncture, there may be a need to develop shared methodologies for future trials in the same way the ONE Study developed a set of standardized clinical protocols to be shared between all partners.18
The state of the art summary on MSC therapy in transplantation in this issue is an important milestone in a rapidly developing field and marks the transition of MSC therapy from early safety trials to trials of efficacy. With MSC therapy becoming widely recognized by clinicians and increasingly researched by patients, it is important for professionals in transplantation to make themselves familiar with the field.
1. Friedenstein AJ, Petrakova KV, Kurolesova AI, et al. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation
2. Friedenstein AJ, Chailakhyan RK, Latsinik NV, et al. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation
3. Horwitz EM, Le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy
4. Franquesa M, Hoogduijn MJ, Reinders ME, et al. Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Fourth Meeting: lessons learned from first clinical trials. Transplantation
5. Munneke JM, Spruit MJ, Cornelissen AS, et al. The potential of mesenchymal stromal cells as treatment for severe steroid-refractory acute graft-versus-host disease: a critical review of the literature. Transplantation
6. Plock JA, Schnider JT, Zhang W, et al. Adipose- and bone marrow-derived mesenchymal stem cells prolong graft survival in vascularized composite allotransplantation. Transplantation
7. Hoogduijn MJ. Immunomodulation by mesenchymal stem cells: lessons from vascularized composite allotransplantation. Transplantation
8. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol
9. Vega A, Martin-Ferrero MA, Del Canto F, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation
10. Noriega DC, Ardura F, Hernandez-Ramajo R, et al. Intervertebral disc repair by allogeneic mesenchymal bone marrow cells: a randomized controlled trial. Transplantation
11. Amado LC, Saliaris AP, Schuleri KH, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A
12. He Y, Zhou S, Liu H, et al. Indoleamine 2, 3-dioxgenase transfected mesenchymal stem cells induce kidney allograft tolerance by increasing the production and function of regulatory T cells. Transplantation
13. Reinders MEJ, van Kooten C, Rabelink TJ, et al. Mesenchymal stromal cell therapy for solid organ transplantation. Transplantation
. 2017 [published online July 12, 2017]. doi: 10.1097/TP.0000000000001879.
14. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy
15. Neofytou E, Deuse T, Beygui RE, et al. Mesenchymal stromal cell therapy: different sources exhibit different immunobiological properties. Transplantation
16. Reinders ME, de Fijter JW, Roelofs H, et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med
17. Haarer J, Johnson CL, Soeder Y, et al. Caveats of mesenchymal stem cell therapy in solid organ transplantation. Transpl Int
18. van der Net JB, Bushell A, Wood KJ, et al. Regulatory T cells: first steps of clinical application in solid organ transplantation. Transpl Int