Can the Therapeutic Advantages of Allogenic Umbilical Cord Blood???Derived Stem Cells and Autologous Bone Marrow???Derived Mesenchymal Stem Cells Be Combined and Synergized?

To the Editor: In recent years, adult stem cells have attracted much attention over their potential applications in regenerative medicine.1,2 This encompasses all stem cells derived from the postnatal state, not the adult body only, and hence would also include umbilical cord blood–derived stem cells.3 Compared with embryonic and fetal stem cells, the application of adult stem cells in clinical therapy is much less ethically contentious.4 Moreover, adult stem cells from an autologous source would also circumvent the immunological barrier in clinical transplantation and negate the need for human leukocyte antigen (HLA) matching,5 as in the case of embryonic and fetal stem cells, which are invariably derived from an allogenic source. Of the diverse array of adult stem cells that have so far been identified, those derived from the bone marrow and umbilical cord blood appear particularly attractive for a number of reasons. Compared with other adult stem cell subpopulations that are relatively scarce and difficult to extract from the human body, these are relatively abundant and easy to isolate.6,7 Moreover, previous studies have also demonstrated that adult stem cells derived from the bone marrow and umbilical cord blood have relatively high proliferative capacity and regenerative potential as well as a more extensive multi-lineage differentiation potential compared with other adult stem cell types.1,6,7 Both these subpopulations of adult stem cells have their inherent advantages and limitations in clinical therapy. For example, several studies have demonstrated an age-related decline in the proliferative capacity and regenerative potential of mesenchymal stem cells (MSC) extracted from bone marrow, which could limit their therapeutic usefulness in older patients.8,9 Presumably, no such limitation exists for stem cells derived from the umbilical cord blood because these are putatively in the neonatal state. Moreover, millions of new births every day produce an excess of discarded human umbilical cord,10 thus making stem cells extracted from these much more abundant and readily available compared with bone marrow–derived MSC. Nevertheless, it must be noted that umbilical cord blood–derived stem cells must be from an allogenic source, unless these were deliberately cryopreserved and stored for a particular newborn individual. Hence, there is ultimately the prospect of immunological rejection on transplantation or transfusion, unlike the case of autologous MSC derived from the bone marrow. Additionally, MSC have also been demonstrated to have immunoprivileged status and immunomodulatory properties11,12 absent in other adult stem cell subpopulations, thus making them ideally suited for transplantation therapy. A novel strategy may therefore be to combine and synergize the complementary therapeutic advantages of umbilical cord blood and bone marrow–derived stem cells in regenerative medicine. This may be achieved either through co-transplantation of both cell types locally at the same site or by simultaneous localized transplantation with transfusion into the peripheral circulation.13 Already, a number of studies have reported that co-transplantation of bone marrow–derived MSC enhanced the engraftment of umbilical cord blood–derived hematopoietic stem cells.14–16 However, all these studies were performed on immunologically deficient NOD/SCID mice,14–16 and it remains unclear whether co-transplantation could yield such a beneficial effect in the presence of an active immune system. The most obvious advantage of co-transplanting bone marrow derived–MSC with umbilical cord blood stem cells is that this could somehow make up for the shortfall in the total numbers of viable MSC that can be extracted from older patients because a certain threshold number of transplanted cells are probably required to achieve optimal efficacy of tissue/organ regeneration. Moreover, the putative neonatal state of umbilical cord blood–derived stem cells can also compensate for the age-related decline in the proliferative capacity and regenerative potential of MSC derived from older patients.8,9 Nevertheless, the major challenge would be to overcome immunological rejection against allogenic umbilical cord blood–derived stem cells. Even with extensive banking of umbilical cord blood–derived stem cells, it is virtually impossible to achieve a perfect HLA match,17 unless that particular individual’s umbilical cord blood cells had been cryopreserved and stored since birth. In this respect, bone marrow–derived MSC could prove particularly useful because these have been demonstrated to possess immunosuppressive properties.11,12 Hence, it is possible that transplanted autologous MSC may mitigate immunological rejection against co-transplanted umbilical cord blood–derived stem cells at the transplantation site. Once adequate tissue/organ regeneration has been achieved and the immunosuppressive effects of the co-transplanted MSC have worn off (i.e., through differentiation), then the engrafted allogenic umbilical cord blood stem cells may gradually be killed off by the recipient’s immune system while being replaced by proliferating autologous cells (i.e., co-transplanted MSC). Another possibility is that differentiated lineages may still retain the immuno-modulatory properties of their MSC precursors, as demonstrated by a recent study from our research group.18 Hence, there may be long-term tolerance induction of the allogenic umbilical cord blood cells through the immunomodulatory action of the co-transplanted autologous MSC. Certainly, it can be argued that immunosuppressive drugs can be used instead of co-transplanted MSC. Nevertheless, it must be remembered that the administration of such drugs often have various adverse side effects on patients.19 Moreover, the concentrated localized immunomodulatory effect of co-transplanted MSC at one particular site is preferable to the holistic effect of immunosuppressive drug administration. It may also be worthwhile to look at the possibility of co-transplanting differentiated progenies of allogenic umbilical cord blood stem cells with autologous MSC. The rationale is that paracrine signaling and cellular contacts provided by such differentiated progenies may result in a more conducive environment for directing co-transplanted autologous MSC into a required lineage at the transplantation site, since the natural milieu may already be compromised by the pathological state of the diseased/damaged tissue or organ requiring transplantation therapy. It must be noted that because umbilical cord blood stem cells are from a donated allogenic source, an extended period of time is available to differentiate them into a particular lineage before transplantation. By contrast, such an option is rarely available in the case of autologous MSC because of the urgency of life-saving treatment for the patient. Hence, in this manner, differentiated progenies of umbilical cord blood stem cells can possibly be used as “cellular catalysts” to promote the appropriate differentiation of co-transplanted autologous MSC in situ, which could in turn enhance their subsequent engraftment and integration within recipient tissues/organs. Nevertheless, as highlighted in our previous article,20 there are various challenges faced with transplanting differentiated cells, such as their lower proliferative capacity, higher antigenicity, and more complex nutritional requirement, which in turn could compromise their survival within the adverse pathological environment of the transplantation site. Hence, it is imperative to find a subtle balance somewhere between the undifferentiated and fully differentiated state20 of umbilical cord blood–derived stem cells that would be optimal for co-transplantation with MSC. Besides co-transplantation, an alternative strategy may be to carry out simultaneous transplantation and transfusion of both stem cell types.13 In this case, hematopoietic stem cells derived from umbilical cord blood could be more suited for transfusion, whereas bone marrow–derived MSC could be more suited for transplantation in situ at the site of tissue/organ damage. Perhaps it may be worthwhile for both stem cell types to be committed to different lineages. For example, the repair of a myocardially infarcted heart would require both the regeneration of damaged cardiac muscles as well as neovascularization.21 Hence, it could be advantageous to transplant cardiomyocyte precursors derived from bone marrow MSC22 directly in situ within the damaged myocardium, while at the same time transfusing endothelial progenitors23 derived from umbilical cord blood into the peripheral circulation. In this case, the use of recombinant DNA transfection24 or other newly developed technology for gene modulation such as protein transduction domains fusion transcription factors25,26 may obviate the need for extended durations of ex vivo culture to achieve lineage commitment. The recent identification and characterization of various chemokines and cytokines involved in stem cell migration and homing open up an exciting possibility for their application in transplantation/transfusion therapy.27,28 For example, the transplanted MSC may be delivered on tissue-engineered scaffolds that are designed for the controlled release of specific homing factors such as SDF-1.29 Another alternative may be to stimulate or genetically modulate the transplanted MSC to copiously secrete homing factors such as SDF-129 to encourage the migration and homing of transfused umbilical cord blood stem cells within the peripheral circulation. At the same time, it may also be advantageous to prestimulate the transfused umbilical cord blood stem cells to strongly express surface receptors specific to homing factors such as SDF-1. Of particular interest would be CXCR-4. In the seminal study of Peled et al.,30 it was demonstrated that pretreatment with stem cell factor and interleukin-6 upregulated CXCR-4 expression on CD34+ cells, which in turn potentiated SDF-1–induced migration and engraftment in primary and secondary transplanted mice. Hence, there are indeed many exciting possibilities in combining and synergizing the therapeutic advantages of allogenic umbilical cord blood–derived stem cells and autologous bone marrow–derived mesenchymal stem cells. This would certainly warrant further investigation.