STEM CELL TRANSPLANTATION: Edited by Elke Eggenhofer
Stem cells of mesenchymal origin, for example mesenchymal stem cells (MSC) and multipotent adult progenitor cells (MAPC) are emerging as a promising cell population for novel therapeutic regimens. MSC have been utilized in preclinical models and clinical trials for more than three decades. Although MSC-based products are still awaiting European market authorisation, MSC-based cell therapy products have been approved in other markets worldwide. South Korea has granted marketing authorization for two MSC-based products; in 2011 Cartistem became the world's first commercial, allogenic, off-the-shelf MSC-based product followed by HeartiCellgram. Following suit, in May 2012 authorization was awarded by Health Canada to Osiris Therapeutics Inc. for Prochymal. To-date, these products are approved for the treatment of traumatic and degenerative osteoarthritis, acute myocardial infarction (AMI) and graft-versus-host disease (GvHD). More recently, the first clinical trials designed to assess the immunosuppressive potential of MSC in organ transplantation have been initiated. In this issue, the potential contribution of MSC to all aspects of organ and tissue transplantation is discussed.
The only medical option for many patients suffering from end-stage renal disease, severe diabetes, advanced heart disease, and liver disease is an organ transplant. In the last few years, there has been a concerted effort to improve the management of organ rejection and indeed, the majority of patients can be kept stable. Although it is a clinical aspiration to achieve a drug-free, stable tolerance in organ transplant recipients to their donor grafts, it remains a rare event. Patients must face the reality of a continuing regime of immunosuppression, which has a major impact on their quality of life. For example, organ transplant patients are up to 100-times more likely to develop skin cancer when compared with the general population (www.ucsfhealth.org). In addition, current multidrug immunosuppression protocols of calcineurin inhibitors, steroids, antibodies, glucocorticoids, fusion-proteins and small molecules are ineffective in preventing chronic rejection. Understandably, there is a strong motivation to explore novel therapeutic strategies that promote graft tolerance. One very promising field is cell therapy. A variety of haematological cell populations are being investigated in the context of organ transplantation and immunomodulation, for example regulatory T cells (Treg), regulatory B cells (Breg), tolerogenic dendritic cells (tolDC) and regulatory cells of myeloid origin, such as macrophages (Mreg) and myeloid-derived suppressor cells (MDSC). Already, encouraging results have been obtained from these cell types with promising preclinical data and remarkable outcomes in single patient studies.
An inherent shortcoming of haematological derived cells that has affected their broader adoption into routine clinical use is that sufficient cell expansion or selection is impractical given the time constraints of routine postmortal organ allocation and transport. In contrast, MSC can be routinely isolated and expanded from bone marrow or almost any other tissue using scalable good manufacturing practice-techniques and are amenable to cryostorage. This off-the-shelf potential makes them especially suited to clinical applications.
In this issue of Current Opinion in Organ Transplantation, we have summarised and outlined the potential contribution of MSC to the complications associated with organ transplantation including initial organ damage resulting from explantation, ischemia and reperfusion damage and finally organ damage via acute and chronic rejection (Fig. 1).
Initial organ damage caused by organ preservation is a problem. Attempts have been made recently to improve this situation, for example the use of ex-vivo perfusion systems. In this review article, Dirk Raemdonck's group (pp. 24–33) from Leuven discusses the potential use of MSCs in organ preservation, summarizes the most recent developments and underlines the clinical challenges. Martina Seiffert's group (pp. 34–43) from Berlin focuses on the beneficial influence of MSC in reducing early ischemia reperfusion injury (IRI) and describes the advantages for translational applications. A familiar obstacle of successfully organ transplantation is acute rejection. MSC has been shown to ameliorate rejection reactions in various animal models and are currently being assessed in initial clinical trials. Marlies Reinders (pp. 44–50) from Leiden, one of the first investigators to examine the clinical use of MSC in kidney transplantation, outlines the current status. Federica Casiraghi (pp. 51–58) from Giuseppe Remuzzi's laboratory contributes their experience of the emerging field of utilising MSC in the prevention of chronic rejection. The promise offered by MSC in the evolving field of diabetes research is summarised by James Reading (pp. 59–64), whom details the use of a MSC-based immunosuppression scheme in the transplantation of insulin-producing islet cells. Finally, Richard Verbeek (pp. 65–70) from Rotterdam contributes a review article outlining the technical, logistical and regulatory challenges of using a MSC product in a clinical setting.
Although MSC technology has a vast potential to revolutionize organ transplantation, particularly in relation to organ pretreatment, ischemia reperfusion damage, acute and chronic rejection episodes only now are the first clinical trials using MSC underway. One must be mindful that in many areas, MSC have yet to be thoroughly and critically assessed; further preclinical and clinical investigations will be absolutely necessary to answer the question of whether MSC in transplantations are truly ‘the one for all seasons’.
Sincere thanks to Dr Christian Johnson for critical reading of the manuscript.
Conflicts of interest
There are no conflicts of interest.