To the Editor
A pilot study by Wu et al. (1) suggests that umbilical cord–derived mesenchymal stem cells (UCMSCs) promote hematopoietic engraftment when cotransplanted with cord blood (CB) cells (Fig. 1A). The authors make good use of two somatic stem cells, both derived from umbilical cord. Together with the establishment of their UCMSC bank, their trial appears to be potentially meaningful for future development of UCMSC cotransplantation.
A recent article by de Lima et al. (2) demonstrates that hematopoietic engraftment is improved by transplantation of CB cells that are expanded ex vivo with allogeneic bone marrow–derived MSCs (BMMSCs). In this study (2), two CB units were transplanted: one was an expanded CB unit and the other was an unmanipulated CB unit (Fig. 1B). Although BMMSCs were used ex vivo only (2), expanded CB in combination with unmanipulated CB significantly improved engraftment compared with unmanipulated CB only. Based on these findings, it would be interesting to investigate whether addition of ex vivo expanded CB to the pilot study setting by Wu et al. (1) would further improve engraftment (Fig. 1C).
The study by de Lima et al. (2) appears to be safe and effective, because ex vivo expanded CB unit would contribute to rapid recovery of hematopoiesis. However, this study raises some concerns. (i) CB was expanded under culture condition with cytokines including granulocyte colony-stimulating factor, which would expand myeloid progenitor cells at the expense of long-term hematopoietic stem cells (LT-HSCs) (Fig. 1B). Because long-term repopulation has been shown to be dependent on unmanipulated CB, there might be a long-term risk of cytopenia. (ii) Due to reduced percentage of lymphocytes in expanded CB described by de Lima et al. (2), there might be an increased risk of viral infection. Regarding (i), recent evidence suggests that in vitro maintenance of LT-HSCs is possible by dual inhibition (2i) of both glycogen synthase kinase-3 and mammalian target of rapamycin, without use of cytokines that promote differentiation of LT-HSCs (3). Although LT-HSCs were shown to be preserved up to 7 days, “2i for HSCs” (4) would be effective under culture condition even without serum or feeders. As mentioned above, if unmanipulated CB unit as well as expanded CB unit were to be transplanted with UCMSCs, these two concerns might be resolved (Fig. 1C).
Our previous work (5) has demonstrated that, in a nonhuman primate model, cotransplantation with BMMSCs improves engraftment of HSCs after autologous intra–bone marrow transplantation. The present study (1) is different from our study (5) in several points; regarding cotransplantation with MSCs in HSC transplantation, future options may include (a) cell source (origin) of MSCs and (b) route of administration of MSCs.
Regarding (a), there may be some differences between the property of BMMSCs and that of UCMSCs. Maintenance of hematopoiesis would be possible not only via physical interaction with HSCs but also via secreted factors, such as stromal cell–derived factor-1, stem cell factor, or angiopoietin-1. Besides, recent evidence suggests that prostaglandin E2 (PGE2) is involved in HSC survival and proliferation (6) and also indicates that PGE2 is shown to significantly enhance engraftment of human CB cells in a nonhuman primate model (7). More recently, it has been suggested that bone marrow–derived mesenchymal progenitor cells facilitate recovery of HSCs by producing PGE2 (8); thus, it would be of interest to test PGE2 production (9) by UCMSCs. Are UCMSCs superior to BMMSCs regarding PGE2 production? Would it be better to cotransplant CB and UCMSCs, both derived from the same donor?
Regarding (b), there are mainly two ways: intravenous injection and intra–bone marrow injection. Is there any evidence of cell/tissue–specific distribution of UCMSCs after intravenous injection, as described in the case of BMMSCs (10)? If UCMSCs are found to be trapped in tissues, such as the lung, UCMSCs should be injected (not before) after CB transplantation to reduce the loss of CB homing to BM (i.e., to not trap CB and UCMSCs). On the contrary, there is an advantage in intravenous injection, as shown in a radiation-induced gastrointestinal syndrome mice model (11). Future studies should clarify the potential risk of tumor-supportive niche created by UCMSCs.
Although there are still many unanswered questions regarding UCMSCs, the advantages of using UCMSCs (12, 13) are evident. Further elucidation of UCMSCs properties (especially those that are distinct from BMMSCs (14)) will provide substantial advances in the field of transplantation medicine.
Juan Carlos Izpisua Belmonte1,2
1 Gene Expression Laboratory
The Salk Institute for Biological Studies
La Jolla, CA
2Center of Regenerative
Medicine in Barcelona
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