Challenges and Controversies in Human Mesenchymal Stem Cell Therapy
3.2. MSCs to Treat or Prevent Graft-versus-Host DiseaseGraft-versus-host disease (GvHD) accompanies allogeneic hematopoietic stem cell transplantation (HSCT) in many patients. In GvHD treatment, the corticosteroids are used; however, this therapy is not effective in all patients [8]. Immunomodulatory properties of MSCs reported in experimental studies suggest their application in GvHD treatment. Indeed, recently MSC transplantation was performed to prevent or to treat GvHD especially in those patients who are unresponsive to steroids [24]. However, despite of MSC applications in many clinical trials, the controversy still exists for the profits of such a therapy. Although the reduction of inflammatory processes is noticed after MSC implantation, downregulation of immune response could augment the chance of infections, especially in patients receiving immunosuppressive therapy after HSCT [25]. It was reported that the infusion of MSCs might dangerously constrain antimicrobial immune response [26]. von Bahr et al. have shown enhanced complications in a retrospective study in GvHD patients due to the infections in a short period of time after different source derived (BM/PBSCs/CB) MSC transplantation, causing the mortality to reach 54% [27]. The infection-related mortality was high even after GvHD determination. It may be related to the long immunosuppressive effect of MSCs. The clinical trial announced by Ning et al. showed that the occurrence of acute and chronic GvHD in patients after MSC transplantation was lower than in patients without MSC graft, but the episodes of severe infections were higher in patients who have received HSCT and bone marrow-derived MSCs than in the control group not receiving MSCs. Among patients, two of them manifested CMV interstitial pneumonia and/or fungal infection [28]. Forslöw et al. suggest an increased susceptibility to pneumonia observed in patients with GvHD after MSC infusion [29]. The retrospective study of patients with steroid-refractory GvHD receiving MSCs announced high CMV peak viral load [27]. This is the contradiction with earlier in vitro experiments which depicted that cytotoxic T cells against CMV were restricted to BM-MSC effect [30]. Recently, Thanunchai et al. have postulated that in viral infections human BM-MSCs might also act as viral transmitters [31]. Moreover, in different experimental models it was shown that BM-MSCs encourage tumor growth by modulating the tumor microenvironment [32, 33]. In a pilot clinical study using MSCs to prevent GvHD in patients with hematologic malignancies, MSCs decreased GvHD development but the relapse rate in patients was over the control group. Out of 10 patients, 6 of them in the MSC group suffered from tumor relapse in comparison to 3 of 15 in the control group not receiving MSCs [28]. The protumorigenic effects revealed by MSCs are probably related to their immunosuppressive properties, the modulation of tumor stroma, and their ability to transform themselves into malignant cells. However, the experiments confirming the tumorigenic potential of MSCs were conducted on rodent models. Up to now, there is no existing data displaying malignant transformation of human MSCs. Moreover, it is not clear whether human MSC aneuploidy is not related with senescence or transformed population of cells [34]. The existent data concerning the direct in vitro transformation of MSCs were retracted due to contamination with other cell lines. It has been also reported that transplantation of MSCs from diverse sources (BM, placenta, or umbilical cord blood) to haploidentical mice did not prevent or treat GvHD [35]. The suggestion exists that MSCs may lose their immunosuppressive properties in mismatched settings, which was proved on murine cells [36]. Furthermore, the Muroi et al. study showed that grafted BM-MSCs in the phase II/III study for acute GvHD does not protect the development of chronic GvHD [37].Based on the above mentioned studies, it needs to be highlighted that MSC transplantation for GvHD prevention or therapy is relatively safe and efficient in steroid-refractory GvHD, but infections remain a major risk of patients. Furthermore, it was shown that MSCs transplanted for established GvHD can cause an increased relapse [28]. In the recent paper published by Ringden et al.’s group, the authors mention several adverse effects occurring after transplantation of decidual placenta-derived MSCs in the treatment of GvHD. Among them, relapse; pneumonia; bacterial, viral, and fungal infection; and graft failure are listed [38]. It seems that the new strategy supporting a high rate effect of MSCs against GvHD with a low adverse effect to the patient is warranted in large-scale randomized studies. The research carried by different laboratories focuses on the development of new MSC drugs. One of the first registered MSC-based drugs recommended to use for treatment of GvHD was Prochymal. Recently, Mesoblast recruited patients for clinical phase 3 for treatment of GvHD and others like chronic heart failure and chronic low back pain. The company developed the strategy of isolation and banking of BM-MSCs derived from healthy donors. However, this product is not yet approved by FDA. Similarly iPSC-derived MSCs were proposed by Cynata’s therapeutics. Investigation is within clinical phase 1; however, it is still hard to evaluate the results due to the early stage of research.
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