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Going straight to the point: intra-BM injection of hematopoietic progenitors

Bone Marrow Transplantation volume 45, pages 1127–1133 (2010)Cite this article

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Abstract

Intra-BM injection (IBMI) has been used clinically as a technique to deliver medications, blood products and fluids to critically ill children and war-wounded soldiers. Interest in IBMI has now been renewed in the setting of hematopoietic cell transplantation, in particular when umbilical cord blood is the graft source. Clinical studies have not yet unequivocally shown improvement in hematopoietic recovery. However, most intriguing is the observation, both in the clinical setting and in murine models, that the IBMI delivery of hematopoietic grafts and lymphocytes may reduce in the risk of acute GVHD. The underlying mechanism of the reduced risk of GVHD requires further investigation. In this study, we review the rationale as well as the clinical and pre-clinical data that support the study of IBMI as a method to deliver hematopoietic cells.

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References

  1. Spivey WH . Intraosseous infusions. J Pediatr 1987; 111: 639–643.

    Article  CAS  PubMed  Google Scholar 

  2. Smith R, Davis N, Bouamra O, Lecky F . The utilisation of intraosseous infusion in the resuscitation of paediatric major trauma patients. Injury 2005; 36: 1034–1038; discussion 1039.

    Article  PubMed  Google Scholar 

  3. Josefson A . A new method of treatment-intraossal injections. Acta Medica Scandinavica 1934; 81: 550–564.

    Article  Google Scholar 

  4. Tocantins L, O'NEILL J, Jones H . Infusions of blood and other fluids via the bone marrow: application in pediatrics. JAMA 1941; 117: 1229.

    Article  Google Scholar 

  5. Frassoni F, Gualandi F, Podesta M, Raiola AM, Ibatici A, Piaggio G et al. Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncol 2008; 9: 831–839.

    Article  CAS  PubMed  Google Scholar 

  6. Brunstein CG, Barker JN, Weisdorf DJ, Defor TE, McKenna D, Chong SY et al. Intra-BM injection to enhance engraftment after myeloablative umbilical cord blood transplantation with two partially HLA-matched units. Bone Marrow Transplant 2009; 43: 935–940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301: 2349–2361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rowe JM . Optimal management of adults with ALL. Br J Haematol 2009; 144: 468–483.

    Article  PubMed  Google Scholar 

  9. Bosticardo M, Marangoni F, Aiuti A, Villa A, Grazia Roncarolo M . Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood 2009; 113: 6288–6295.

    Article  CAS  PubMed  Google Scholar 

  10. Sullivan KM, Parkman R, Walters MC . Bone marrow transplantation for non-malignant disease. Hematology Am Soc Hematol Educ Program 2000, 319–338.

    Article  Google Scholar 

  11. Filipovich A . Hematopoietic cell transplantation for correction of primary immunodeficiencies. Bone Marrow Transplant 2008; 42 (Suppl 1): S49–S52.

    Article  PubMed  Google Scholar 

  12. Karanes C, Nelson GO, Chitphakdithai P, Agura E, Ballen KK, Bolan CD et al. Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant 2008; 14 (9 Suppl): 8–15.

    Article  PubMed  Google Scholar 

  13. Sauter C, Barker JN . Unrelated donor umbilical cord blood transplantation for the treatment of hematologic malignancies. Curr Opin Hematol 2008; 15: 568–575.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Harousseau JL, Moreau P . Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med 2009; 360: 2645–2654.

    Article  CAS  PubMed  Google Scholar 

  15. Goldstone AH . Transplants in adult ALL--? Allo for everyone. Biol Blood Marrow Transplant 2008; 15 (1 Suppl): 7–10.

    Google Scholar 

  16. van Hennik PB, de Koning AE, Ploemacher RE . Seeding efficiency of primitive human hematopoietic cells in nonobese diabetic/severe combined immune deficiency mice: implications for stem cell frequency assessment. Blood 1999; 94: 3055–3061.

    CAS  PubMed  Google Scholar 

  17. Cui J, Wahl RL, Shen T, Fisher SJ, Recker E, Ginsburg D et al. Bone marrow cell trafficking following intravenous administration. Br J Haematol 1999; 107: 895–902.

    Article  CAS  PubMed  Google Scholar 

  18. Cashman JD, Eaves CJ . High marrow seeding efficiency of human lymphomyeloid repopulating cells in irradiated NOD/SCID mice. Blood 2000; 96: 3979–3981.

    CAS  PubMed  Google Scholar 

  19. Hwang WY, Samuel M, Tan D, Koh LP, Lim W, Linn YC . A meta-analysis of unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients. Biol Blood Marrow Transplant 2007; 13: 444–453.

    Article  PubMed  Google Scholar 

  20. Shi-Xia X, Xian-Hua T, Xiang-Feng T . Unrelated umbilical cord blood transplantation and unrelated bone marrow transplantation in children with hematological disease: a meta-analysis. Pediatr Transplant 2009; 13: 278–284.

    Article  PubMed  Google Scholar 

  21. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 2007; 369: 1947–1954.

    Article  PubMed  Google Scholar 

  22. Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 1998; 339: 1565–1577.

    Article  CAS  PubMed  Google Scholar 

  23. Migliaccio AR, Adamson JW, Stevens CE, Dobrila NL, Carrier CM, Rubinstein P . Cell dose and speed of engraftment in placental/umbilical cord blood transplantation: graft progenitor cell content is a better predictor than nucleated cell quantity. Blood 2000; 96: 2717–2722.

    CAS  PubMed  Google Scholar 

  24. Barker JN, Rocha V, Scaradavou A . Optimizing unrelated donor cord blood transplantation. Biol Blood Marrow Transplant 2008; 15 (1 Suppl): 154–161.

    Google Scholar 

  25. Koestenbauer S, Zisch A, Dohr G, Zech NH . Protocols for hematopoietic stem cell expansion from umbilical cord blood. Cell Transplant 2009; 18: 1059–1068.

    Article  PubMed  Google Scholar 

  26. Hofmeister CC, Zhang J, Knight KL, Le P, Stiff PJ . Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche. Bone Marrow Transplant 2007; 39: 11–23.

    Article  CAS  PubMed  Google Scholar 

  27. Haspel RL, Ballen KK . Double cord blood transplants: filling a niche? Stem Cell Rev 2006; 2: 81–86.

    PubMed  Google Scholar 

  28. Majhail NS, Brunstein CG, Wagner JE . Double umbilical cord blood transplantation. Curr Opin Immunol 2006; 18: 571–575.

    Article  CAS  PubMed  Google Scholar 

  29. Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood 2007; 110: 3064–3070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH et al. Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood 2009; 114: 4293–4299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Broxmeyer HE, Hangoc G, Cooper S, Campbell T, Ito S, Mantel C . AMD3100 and CD26 modulate mobilization, engraftment, and survival of hematopoietic stem and progenitor cells mediated by the SDF-1/CXCL12-CXCR4 axis. Ann NY Acad Sci 2007; 1106: 1–19.

    Article  CAS  PubMed  Google Scholar 

  32. Ratajczak MZ, Reca R, Wysoczynski M, Yan J, Ratajczak J . Modulation of the SDF-1-CXCR4 axis by the third complement component (C3)--implications for trafficking of CXCR4+ stem cells. Exp Hematol 2006; 34: 986–995.

    Article  CAS  PubMed  Google Scholar 

  33. Hagglund H, Ringden O, Agren B, Wennberg L, Remberger M, Rundquist L et al. Intraosseous compared to intravenous infusion of allogeneic bone marrow. Bone Marrow Transplant 1998; 21: 331–335.

    Article  CAS  PubMed  Google Scholar 

  34. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, Miller JS et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105: 1343–1347.

    Article  CAS  PubMed  Google Scholar 

  35. Rubinstein P, Dobrila L, Rosenfield RE, Adamson JW, Migliaccio G, Migliaccio AR et al. Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc Natl Acad Sci USA 1995; 92: 10119–10122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kraft D, Song L, Crocker M, Moseley A, Long M, Vina R et al. 113: the ìMarrow-Minerî: efficacy of a novel, minimally invasive bone marrow harvesting device in pre-clinical evaluation & first human experience. Biol Blood Marrow Transplant 2008; 14 (2 Suppl): 44.

    Article  Google Scholar 

  37. Kushida T, Inaba M, Hisha H, Ichioka N, Esumi T, Ogawa R et al. Intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice. Blood 2001; 97: 3292–3299.

    Article  CAS  PubMed  Google Scholar 

  38. Mazurier F, Doedens M, Gan OI, Dick JE . Rapid myeloerythroid repopulation after intrafemoral transplantation of NOD-SCID mice reveals a new class of human stem cells. Nat Med 2003; 9: 959–963.

    Article  CAS  PubMed  Google Scholar 

  39. Zhong JF, Zhan Y, Anderson WF, Zhao Y . Murine hematopoietic stem cell distribution and proliferation in ablated and nonablated bone marrow transplantation. Blood 2002; 100: 3521–3526.

    Article  CAS  PubMed  Google Scholar 

  40. Yahata T, Ando K, Sato T, Miyatake H, Nakamura Y, Muguruma Y et al. A highly sensitive strategy for SCID-repopulating cell assay by direct injection of primitive human hematopoietic cells into NOD/SCID mice bone marrow. Blood 2003; 101: 2905–2913.

    Article  CAS  PubMed  Google Scholar 

  41. Wang J, Kimura T, Asada R, Harada S, Yokota S, Kawamoto Y et al. SCID-repopulating cell activity of human cord blood-derived CD34- cells assured by intra-bone marrow injection. Blood 2003; 101: 2924–2931.

    Article  CAS  PubMed  Google Scholar 

  42. Castello S, Podesta M, Menditto VG, Ibatici A, Pitto A, Figari O et al. Intra-bone marrow injection of bone marrow and cord blood cells: an alternative way of transplantation associated with a higher seeding efficiency. Exp Hematol 2004; 32: 782–787.

    Article  PubMed  Google Scholar 

  43. Scadden DT . The stem-cell niche as an entity of action. Nature 2006; 441: 1075–1079.

    Article  CAS  PubMed  Google Scholar 

  44. Watt FM, Hogan BL . Out of Eden: stem cells and their niches. Science 2000; 287: 1427–1430.

    Article  CAS  PubMed  Google Scholar 

  45. Wilson A, Trumpp A . Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 2006; 6: 93–106.

    Article  CAS  PubMed  Google Scholar 

  46. Schofield R . The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 1978; 4: 7–25.

    CAS  PubMed  Google Scholar 

  47. Adams GB, Scadden DT . The hematopoietic stem cell in its place. Nat Immunol 2006; 7: 333–337.

    Article  CAS  PubMed  Google Scholar 

  48. Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 2009; 457: 92–96.

    Article  CAS  PubMed  Google Scholar 

  49. Kiel MJ, Morrison SJ . Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 2008; 8: 290–301.

    Article  CAS  PubMed  Google Scholar 

  50. Nervi B, Link DC, DiPersio JF . Cytokines and hematopoietic stem cell mobilization. J Cell Biochem 2006; 99: 690–705.

    Article  CAS  PubMed  Google Scholar 

  51. Dar A, Kollet O, Lapidot T . Mutual, reciprocal SDF-1/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in NOD/SCID chimeric mice. Exp Hematol 2006; 34: 967–975.

    Article  CAS  PubMed  Google Scholar 

  52. Lapidot T, Kollet O . The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia 2002; 16: 1992–2003.

    Article  CAS  PubMed  Google Scholar 

  53. Papayannopoulou T, Priestley GV, Nakamoto B . Anti-VLA4/VCAM-1-induced mobilization requires cooperative signaling through the kit/mkit ligand pathway. Blood 1998; 91: 2231–2239.

    CAS  PubMed  Google Scholar 

  54. Ramirez P, Rettig MP, Uy GL, Deych E, Holt MS, Ritchey JK et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood 2009; 114: 1340–1343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pelus LM, Fukuda S . Peripheral blood stem cell mobilization: the CXCR2 ligand GRObeta rapidly mobilizes hematopoietic stem cells with enhanced engraftment properties. Exp Hematol 2006; 34: 1010–1020.

    Article  CAS  PubMed  Google Scholar 

  56. Christopherson II KW, Hangoc G, Mantel CR, Broxmeyer HE . Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 2004; 305: 1000–1003.

    Article  CAS  PubMed  Google Scholar 

  57. Priestley GV, Scott LM, Ulyanova T, Papayannopoulou T . Lack of alpha4 integrin expression in stem cells restricts competitive function and self-renewal activity. Blood 2006; 107: 2959–2967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lapidot T, Dar A, Kollet O . How do stem cells find their way home? Blood 2005; 106: 1901–1910.

    Article  CAS  PubMed  Google Scholar 

  59. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 2005; 201: 1307–1318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kahn J, Byk T, Jansson-Sjostrand L, Petit I, Shivtiel S, Nagler A et al. Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation. Blood 2004; 103: 2942–2949.

    Article  CAS  PubMed  Google Scholar 

  61. Bonig H, Wundes A, Chang KH, Lucas S, Papayannopoulou T . Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab. Blood 2008; 111: 3439–3441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ohno N, Kajiume T, Sera Y, Sato T, Kobayashi M . Short-term culture of umbilical cord blood-derived CD34 cells enhances engraftment into NOD/SCID mice through increased CXCR4 expression. Stem Cells Dev 2009; 18: 1221–1226.

    Article  CAS  PubMed  Google Scholar 

  63. Kobune M, Kawano Y, Takahashi S, Takada K, Murase K, Iyama S et al. Interaction with human stromal cells enhances CXCR4 expression and engraftment of cord blood Lin(−)CD34(−) cells. Exp Hematol 2008; 36: 1121–1131.

    Article  CAS  PubMed  Google Scholar 

  64. Dao MA, Creer MH, Nolta JA, Verfaillie CM . Biology of umbilical cord blood progenitors in bone marrow niches. Blood 2007; 110: 74–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Meng ZT, Gao JT, Lu SH, Yan X, Li YH, Yang Z et al. Intra-bone marrow infusion of human cord blood hematopoietic stem/progenitor cells improves hematopoietic reconstitution in NOD-SCID mice. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2009; 17: 1010–1015.

    CAS  PubMed  Google Scholar 

  66. Nakamura K, Inaba M, Sugiura K, Yoshimura T, Kwon AH, Kamiyama Y et al. Enhancement of allogeneic hematopoietic stem cell engraftment and prevention of GVHD by intra-bone marrow bone marrow transplantation plus donor lymphocyte infusion. Stem Cells 2004; 22: 125–134.

    Article  PubMed  Google Scholar 

  67. Nishida T, Hosaka N, Takaki T, Miyake T, Cui W, Inaba M et al. Allogeneic intra-BM-BMT plus adult thymus transplantation from same donor has benefits for long-term survival even after sublethal irradiation or low-dose BM cell injection. Bone Marrow Transplant 2009; 43: 829–837.

    Article  CAS  PubMed  Google Scholar 

  68. Miyake T, Hosaka N, Cui W, Nishida T, Takaki T, Inaba M et al. Adult thymus transplantation with allogeneic intra-bone marrow-bone marrow transplantation from same donor induces high thymopoiesis, mild graft-versus-host reaction and strong graft-versus-tumour effects. Immunology 2009; 126: 552–564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    P A Ramirez & C G Brunstein

  2. Division of Hematology, Department of Pediatrics, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    J E Wagner

  3. Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA

    P A Ramirez, J E Wagner & C G Brunstein

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Correspondence to C G Brunstein.

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Ramirez, P., Wagner, J. & Brunstein, C. Going straight to the point: intra-BM injection of hematopoietic progenitors. Bone Marrow Transplant 45, 1127–1133 (2010). https://doi.org/10.1038/bmt.2010.39

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