Success of umbilical cord blood transplantation (UCBT) has been limited by a high rate of graft failure and delayed hematological recovery. It has been postulated that MSCs have hematopoiesis-supportive properties. Therefore, to overcome the limitation of UCBT, third-party UCB-derived MSCs were co-transplanted in recipients receiving unrelated UCBT. Seven patients received UCB and third-party UCB–MSCs. Hematopoietic recovery and transplantation outcomes were compared with historic controls. There was no acute toxicity associated with the infusion of MSCs. The median day to neutrophil engraftment was 19 days in patients, as compared with 24 days in controls (P=0.03). The median day of platelet engraftment was 47 days and 57 days in patients and controls, respectively (P=0.26). In addition, there was no engraftment failure in the MSC group. The incidence of acute and chronic GVHD was comparable between the two groups. However, veno-occlusive disease and TRM did not occur in the MSC group. Third-party UCB–MSCs infusion was safe and feasible. MSCs may also enhance the engraftment of UCBT and prevent rejection. In addition, MSCs may have a role in decreasing TRM. Randomized, controlled trials are required to confirm these results and longer follow-up will determine the effects of MSCs on the risk of relapse.
As the first successful umbilical cord blood (UCB)-derived hematopoietic SCT was performed in 1988, unrelated donor UCB transplantation (UCBT) has offered many practical advantages as an alternative source of hematopoietic stem cells (HSCs), such as easy procurement without risks to the donor, reduced risk of transmitting infections, fast accessibility and relatively low incidence and severity GVHD. However, the success of UCBT has been limited by the low cell number, which results in a higher rate of graft failure as well as delayed recovery of neutrophils and platelets.1 To overcome these obstacles, several clinical experiments with ex vivo expanded cord blood cells have been explored and a clinical benefit has recently been reported.2, 3
MSCs are capable of giving rise to multiple cell lineages and were initially identified in BM stroma, but recently found to be present in cord blood and adipose tissue as well.4 Because MSCs can be rapidly expanded ex vivo without the loss of their differentiation potential, MSCs have emerged as a promising modality in regenerative medicine. In addition, MSCs have immunomodulatory properties and have been suggested to support BM stroma.5, 6, 7 Therefore, these cells have been explored for use in enhancing engraftment during hematopoietic SCT through human and animal studies. Several clinical studies have reported the facilitation of engraftment by the infusion of MSCs from HSC donors or haploidentical donors to recipients.8, 9
Although MSCs have been considered to have relatively low immunogenecity, recent findings suggest that allogeneic MSCs are immunogenic. Under certain conditions, HLA MHC class I and class II are upregulated on MSCs.10 In addition, evidence suggests that MSCs have the capacity to present antigen and induce effector T-cell responsiveness in vitro.11, 12 Importantly, preclinical models and clinical trials using allogeneic MSCs have demonstrated no adverse events associated with allogeneic MSCs.13, 14 In addition, several studies using third-party MSCs suggest that infusion of third-party MSCs are feasible.13, 15, 16 Therefore, these findings provide attractive possibilities for the use of universal donor MSCs. MSCs can be isolated from various human tissues other than BM, among which UCB is obtained without invasive methods, and thus may be a more appropriate source of third-party MSCs.
In this study, we administered third-party UCB-derived MSCs to enhance engraftment and to prevent rejection in patients undergoing unrelated UCBT.
Patients and methods
From August 2008 to October 2009, children with acute leukemia undergoing unrelated UCBT were enrolled in this study, which explored co-transplantation with third-party UCB-derived ex vivo expanded MSCs (UCB–MSCs). The results of the study were compared with those of historical controls who received UCBT alone. UCBT was performed if no suitable HLA-matched sibling or unrelated donor was available in both groups. UCB units were selected according to a 4–6/6 HLA-A, -B antigen and -DRB1 allele match to the recipient, the cryopreserved total nucleated cell dose (at least 3.0 × 107/kg) and the bank of origin. If no suitable UCB unit with a total nucleated cell count >3.0 × 107/kg or CD34+ cell count >1.7 × 105/kg was available, then double-unit UCBT was performed. Eligible diagnoses for this study included very high-risk ALL, intermediate-risk or high-risk AML and relapsed acute leukemia. This study was approved by the Institutional Review Board of Samsung Medical Center and the Korea Food and Drug Administration and registered at ClinicalTrial.gov with identifier number NCT00823316. Written informed consent was obtained from the patients and their legal guardians.
Conditioning regimen and GVHD prophylaxis
TBI-based conditioning regimens were used and the dose of TBI was 1000 cGy in both study patients and controls. For GVHD prophylaxis, CYA and mycophenolate were administered. Granulocyte CSF was given starting on the day of transplantation in both groups.
Preparation of UCB–MSCs
The UCB–MSCs were separated and maintained as previously described.17 Briefly, UCB was obtained from a full-term delivery with informed maternal consent. UCB was collected in bags containing anticoagulant and express-shipped to MEDIPOST Co, Ltd, (Seoul, Korea). To isolate and culture MSCs, mononuclear cells were isolated from the human UCBs by centrifugation through a Ficoll–Hypaque gradient (d=1.077 g/cm3, Sigma, St Louis, MO, USA). The separated mononuclear cells were washed, suspended in α-minimum essential medium (Gibco BRL, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (Gibco BRL) and seeded at a concentration of 5 × 106 cells/cm2 and into appropriate size of culture vessel (T175 culture flask or 5-layer Cell Stack or 10-layer Cell Stack). Cultures were maintained at 37 °C in a humidified atmosphere containing 5% CO2 with a change of culture medium twice weekly. One to three weeks later, when the monolayer of fibroblast-like adherent cells colonies had reached 80% confluence, the cells were trypsinized (0.25% trypsin, Gibco BRL), washed, resuspended in culture medium (α-minimum essential medium supplemented with 10% fetal bovine serum) and then sub-cultured. These cells were uniformly positive for CD29, CD44, CD73, CD90, CD105 and CD166. In contrast, they were negative for the hematopoietic lineage markers CD34, CD45, CD14 and HLA–DR as confirmed by flow cytometric analysis of expressed surface antigens. These MSCs differentiate into cells for osteogenic, chondrogenic and adipogenic lineages. To assess the potential allo-immune activity of MSCs, allogeneic PBMC were co-cultured with MSCs and then tested the production of IFN-γ. Relative to the amount of IFN-γ produced by PHA-stimulated PBMC, PBMC mixed with MSCs produced only basal levels of the cytokine, indicating that no immune-stimulation was induced by allogeneic MSCs. The immunophenotypic identification and differentiation potential of the human UCB–MSCs were confirmed after cell expansion and freezing. All manufacturing activities, such as mononuclear cell isolation, expansion of MSC, cryopreservation of MSC and thawing, and further expansion of MSC prior to product release were performed in strict compliance with Korea Food and Drug Administration’s good manufacturing practice standards. The MSCs were suspended in 10% dimethyl sulfoxide and 20% fetal bovine serum and then frozen in liquid nitrogen. The viability of the cell pre- and post-thaw was more than 80%. The finally released MSC product for infusion was harvested from cell culture passage 6 and tested negative for bacteria and mycoplasma.
Co-transplantation of UCB–MSCs
UCB–MSCs were infused at a target dose of 1 × 106/kg in four patients and then 5 × 106/kg in three patients sequentially. MSCs were thawed just before infusion. On day 0, patients received the specified MSC dose immediately prior to infusion of the UCB unit. All culture-expanded MSCs used in this study were obtained from the UCB of a single third-party donor. The degree of HLA match between UCB–MSCs and patients was 0/10 in four, 2/10 in one and 3/10 in two patients with a high-resolution typing.
Definition and assessments
Infusion-related adverse events, time to neutrophil and platelet engraftment, severity of acute GVHD and chimerism were evaluated after transplantation. Engraftment was defined as the time point of the first 3 consecutive days with a count >0.5 × 109/L for neutrophils and the first 7 consecutive days with a count of 20 × 109/L for platelets without transfusion support. Engraftment failure was defined as the absence of durable neutrophil recovery at day +30. Acute GVHD was graded 0–IV and chronic GVHD was defined as limited or extensive according to the established criteria.18, 19 Chimerism was evaluated in peripheral blood cells at day +14 and in BM at day +28, +56, +100, +180 and +365 using DNA fingerprint analyses, which were detected by PCR amplification of STR regions. To evaluate the immune reconstitution, lymphocyte sub-populations were measured at days +28, +100, +180 and +365 post-transplantation by immunophenotyping of peripheral blood. The lymphocytes were analyzed for CD3+ T cells, CD4+CD3+ T-helper cells, CD8+CD3+ cytotoxic T cells, CD19+ B cells and CD16+CD56+ natural killer cells.
A cumulative incidence function, with death as a competing event, was used to estimate neutrophil and platelet recovery. For TRM, relapse was the competing event, and for relapse, TRM was the competing event. The Kaplan–Meier method was used to estimate OS. The Mann–Whitney non-parametric U-test was used to compare times with engraftment.
Table 1 shows the characteristics of the seven study patients compared with nine historic controls who received UCBT alone. All transplantations were performed at Samsung Medical Center, Korea. There was no acute toxicity related to the infusion of MSCs and no sign of ectopic tissue formation. There was no significant difference between patients and controls in terms of age at transplantation, underlying disease, disease status prior to the HSCT and number of double-unit UCBT.
The number of infused nucleated cells and CD34+ cells were not different between patients and controls (Table 1). Graft failure occurred in one of nine patients in the control group; however, it did not occur in the patient group (P=0.33). The patient who experienced graft failure received double-unit CBT and the sums of infused nucleated cells and CD34+ cells were 2.9 × 107/kg and 1.0 × 105/kg, respectively. The median time to neutrophil engraftment was 19 days in recipients of MSC and UCB, as compared with 24 days in controls who received UCB alone (P=0.03). The median day of platelet engraftment was 47 days and 57 days in patients and controls, respectively (P=0.26) (Table 1). The median time to engraftment of platelets was not statistically different between the two groups. However, the cumulative incidence of neutrophil engraftment at day +30 and platelet engraftment at day +100 in study patients was significantly higher than in the controls (P<0.01 and P=0.02, respectively) (Figure 1). Although the hematological recovery was more rapid in patients than in controls, the duration of fever within 30 days after transplantation and the incidence of microbiologically documented infection were not different between the two groups (Table 1).
There was no difference between the two groups in immune recovery (Table 2).
The incidence of grade II–IV acute GVHD and extensive chronic GVHD was not different between study patients and controls (Table 1). Veno-occlusive disease (VOD) developed in three of nine controls; however, there was no VOD in study patients (P=0.21). Although there was no TRM in the patient group, two patients died due to TRM in the control group. One death was due to VOD and the other was due to varicella zoster viral encephalitis, which is associated with extensive chronic GVHD. The cumulative incidence of relapse was not significantly different between the two groups (P=0.33). The 2-year-OS rate was 85.7% in the patient group and 55.6% in the control group (P=0.15).
Adult BM is the major source of MSCs for cell therapy, and several clinical and preclinical studies have shown encouraging evidence for the hematopoiesis-supportive functions of BM-derived MSCs.8, 9, 20, 21, 22 However, harvesting BM requires an invasive procedure, and the number, differentiation potential and maximal life span of MSCs from BM decline with age.23, 24, 25 UCB is an alternative source of MSCs and more suitable as a source for third-party MSCs because they can be obtained by a less invasive method. In addition, UCB–MSCs have a longer culture period and higher proliferation capacity than BM–MSCs.26, 27, 28 Wu et al.15 reported that UCB–MSCs are more immunossupressive than BM–MSCs. In animal models, MSCs from BM or UCB have been shown to enhance engraftment of donor HSCs after co-transplantation.21, 29, 30 In our preclinical models, UCB–MSCs have comparable potential with BM–MSCs in the enhancement of HSC engraftment (manuscript in revision). In this context, we explored the safety and efficacy of co-infused third-party UCB-derived MSCs to enhance engraftment and prevent rejection in patients undergoing UCBT.
In the present study, MSCs promoted the early recovery of neutrophils and platelets, and there was no engraftment failure in patients who received MSCs. These results might be due to MSCs supporting the hematopoietic microenvironment and/or releasing soluble factors to enhance engraftment of HSC. It has been shown that MSCs can reconstitute the BM microenvironment after direct injection into the BM.31, 32 In addition, MSCs have been found in BM after systemic infusion in an animal model and can enhance the engraftment of HSCs.33, 34, 35 These results suggest that MSCs can home to BM and support hematopoiesis. However, other recent studies have suggested that soluble factors released by MSCs may also have a role in the enhancement of HSC engraftment based on the observations of faint and transient engraftment of MSCs after systemic infusion. MSCs are known to secrete various growth factors that promote HSC growth and differentiation as well as chemokines and chemokine ligands that are important in HSC homing to BM.36, 37, 38, 39, 40 The exact mechanism of MSCs for enhancing HSC engraftment still remains to be elucidated. Clinical trials have reported that co-transplantation of MSCs from HLA-matched sibling or haploidentical parents was feasible in hematopoietic SCT.41, 42 However, a study of co-transplantation with parental MSCs has shown that MSCs could prevent life threatening GVHD, but did not support hematopoietic engraftment in recipients of allogeneic UCBT.43 Therefore, further studies are required to confirm the effects of MSCs on enhancing the engraftment of HSCs and to evaluate whether these effects may be different according to the origin of MSCs.
Unexpectedly, we also found that there was no early TRM or VOD in study patients. MSCs may have a role in tissue repair or angiogenesis after tissue damage induced by the conditioning regimen. In contrast, the reduction in tissue damage may be due to anti-inflammatory cytokines44 or a combination of these effects. Extensive studies have explored and demonstrated a chemotactic response of MSCs to the site of injury in animal models of cerebral ischemia, TBI and myocardial infarction, and a functional improvement has been observed in clinical studies.45, 46, 47, 48, 49, 50, 51 Ringden et al.52 showed that MSCs were efficacious in the treatment of hemorrhagic cystitis after allogeneic HSCT, and suggested that MSCs can be used to reverse the toxicities caused by chemoradiotherapy. However, there is little evidence showing that clinical benefits are dependent on the differentiation to tissue or direct repair from infused MSCs.53 These findings suggest that soluble factors secreted by MSCs may be able to reduce inflammation or enhance tissue remodeling. Given that all of the study patients received TBI, the findings in the present study are encouraging for additional future studies.
Positive results have been shown in therapeutic trials of MSCs for GVHD treatment.54, 55 In the present study, the incidences of acute and chronic GVHD were not different between the two groups. Although a recent study has shown that parental MSCs decreased the grade III–IV acute GVHD, given the immunosuppressive properties of MSCs, which are upregulated in the inflammatory milieu,56, 57 it may be more appropriate to use them for the treatment rather than the prophylaxis of GVHD.
Although accelerated lymphocyte recovery after co-transplantation with MSCs in haploidentical HSCT has been suggested,9 the immune reconstitution was not different between the two groups. This finding suggests that MSCs at a minimum did not compromise immune reconstitution after transplantation. Importantly, the impact of MSCs on immune recovery needs to be further elucidated through a randomized, controlled study.
The limitation of this study was that the number of study patients was too small to draw a solid conclusion. Although our previous preclinical study showed that the co-transplantation of BM-derived MSCs enhanced the engraftment of HSCs in a MSC dose-dependent manner,20 the impact of MSC dose on engraftment still remains to be determined. Given the safety of MSCs at a dose of 5 × 106/kg in this study, an additional study testing the safety and efficacy of MSCs at a higher dose deserves further consideration.
In conclusion, a third-party UCB-derived MSC infusion was found to be a safe and feasible treatment option. Larger and randomized clinical trials are required to confirm the efficacy of MSCs for enhancing engraftment and reducing TRM in recipients of UCBT. However, the findings of this studies can serve as preliminary data for future studies. Additional studies will elucidate whether MSCs can overcome a cell-dose limitation and eliminate the need for double-unit UCBT. In addition, a longer follow-up will determine the effects of MSCs on the risk of relapse.
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This study was supported by a grant from the National R&D Program Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea (0520290), and by a grant from the Korea Health 21R&D Project, Ministry of Health, Welfare and Family affairs, Republic of Korea (0405-DB00-0101-0016). This paper was presented at the 2011 BMT tandem meeting in Hawaii.
The authors declare no conflict of interest.
MWL, KHY, HHK, SJC, WO and YSY designed the research; SJC, DSK and WO performed the cell culture and expansion; SHL, MHS, HC and KWS performed the clinical trial; SHL and MWL collected and analyzed the data; SHL, MWL, KHY, KWS, HHK, MHS, HC and YSY interpreted and discussed the data; and SHL wrote the manuscript.
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Lee, S., Lee, M., Yoo, K. et al. Co-transplantation of third-party umbilical cord blood-derived MSCs promotes engraftment in children undergoing unrelated umbilical cord blood transplantation. Bone Marrow Transplant 48, 1040–1045 (2013). https://doi.org/10.1038/bmt.2013.7
- mesenchymal stromal cell
- umbilical cord blood transplantation
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