Secondary Logo

Share this article on:

Cotransplantation of MSCs and HSCs

Masuda, Shigeo1; Izpisua Belmonte, Juan Carlos1,2

doi: 10.1097/TP.0b013e318290b0b1
Correspondence

1 Gene Expression Laboratory The Salk Institute for Biological Studies La Jolla, CA

2 Center of Regenerative Medicine in Barcelona Barcelona, Spain

The authors declare no funding or conflicts of interest.

Address correspondence to: Shigeo Masuda, M.D., Ph.D., Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037.

E-mail: smasuda@salk.edu

Received 28 January 2013.

Accepted 1 March 2013.

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.

FIGURE 1

FIGURE 1

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.

Shigeo Masuda

1

Juan Carlos Izpisua Belmonte1,2

1 Gene Expression Laboratory

The Salk Institute for Biological Studies

La Jolla, CA

2Center of Regenerative

Medicine in Barcelona

Barcelona, Spain

Back to Top | Article Outline

REFERENCES

1. Wu KH, Sheu JN, Wu HP, et al. Cotransplantation of umbilical cord-derived mesenchymal stem cells promote hematopoietic engraftment in cord blood transplantation: a pilot study. Transplantation 2013; 95: 773.
2. de Lima M, McNiece I, Robinson SN, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med 2012; 367: 2305.
3. Huang J, Nguyen-McCarty M, Hexner EO, et al. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med 2012; 18: 1778.
4. Masuda S, Li M, Izpisua Belmonte JC. Niche-less maintenance of HSCs by 2i. Cell Res 2013; 23: 458.
5. Masuda S, Ageyama N, Shibata H, et al. Cotransplantation with MSCs improves engraftment of HSCs after autologous intra-bone marrow transplantation in nonhuman primates. Exp Hematol 2009; 37: 1250.
6. Hoggatt J, Singh P, Sampath J, et al. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 2009; 113: 5444.
7. Goessling W, Allen RS, Guan X, et al. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models. Cell Stem Cell 2011; 8: 445.
8. Ikushima YM, Arai F, Hosokawa K, et al. Prostaglandin E2 regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells. Blood 2013; 121: 1995.
9. Lin HD, Bongso A, Gauthaman K, et al. Human Wharton’s Jelly stem cell conditioned medium enhances freeze-thaw survival and expansion of cryopreserved CD34+ cells. Stem Cell Rev 2013; 9: 172.
10. Devine SM, Cobbs C, Jennings M, et al. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 2003; 101: 2999.
11. Saha S, Bhanja P, Kabarriti R, et al. Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice. PLoS One 2011; 6: e24072.
12. Wu KH, Chan CK, Tsai C, et al. Effective treatment of severe steroid-resistant acute graft-versus-host disease with umbilical cord-derived mesenchymal stem cells. Transplantation 2011; 91: 1412.
13. Chan CK, Wu KH, Lee YS, et al. The comparison of interleukin 6-associated immunosuppressive effects of human ESCs, fetal-type MSCs, and adult-type MSCs. Transplantation 2012; 94: 132.
14. Bianco P, Cao X, Frenette PS, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med 2013; 19: 35.
© 2013 Lippincott Williams & Wilkins, Inc.