Advertisement

MSCs for Enhancement of Hematopoietic Progenitor Cell Engraftment and Poor Graft Function

  • Paolo F. Caimi
  • Hillard M. Lazarus
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

Engraftment failure is a rare but life-threatening complication of hematopoietic cell transplantation (HCT). Newer approaches to HCT, including use of haploidentical donors, umbilical cord blood (UCB) transplant, nonmyeloablative and reduced-intensity conditioning regimens, appear to have an increased risk of graft failure. Multipotent mesenchymal stromal cells (MSCs) are essential bone marrow components that have the potential to differentiate in vitro into tissues along mesenchymal lineages, including bone marrow stroma. This regenerative potential, coupled with the capability to secrete cytokines and growth factors, suggests that MSCs would facilitate and promote hematopoiesis. Moreover, MSCs have immunoregulatory properties and thus could have an additional application in the setting of HCT by reducing both graft rejection and graft-versus-host disease. Initial trials have demonstrated the safety and feasibility of infusion of ex vivo-expanded autologous and allogeneic MSCs. Results from these early trials suggested MSCs may enhance hematopoiesis when infused at the time of HCT; however, subsequent trials have not yet provided confirmation that MSCs accelerate hematopoietic recovery when given shortly after HCT. Ongoing research initiatives include use of MSC infusions for patients who have some evidence of regenerating marrow but have delayed or incomplete hematopoiesis.

Keywords

Umbilical Cord Blood Acute GVHD Hematopoietic Cell Transplantation Multipotent Mesenchymal Stromal Cell Bone Marrow Stroma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Copelan EA (2006) Hematopoietic stem-cell transplantation. N Engl J Med 354:1813–1826PubMedCrossRefGoogle Scholar
  2. 2.
    Leung AY, Kwong YL (2010) Haematopoietic stem cell transplantation: current concepts and novel therapeutic strategies. Br Med Bull 93:85–103PubMedCrossRefGoogle Scholar
  3. 3.
    Ho VT, Soiffer RJ (2001) The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 98:3192–3204PubMedCrossRefGoogle Scholar
  4. 4.
    Maitra B, Szekely E, Gjini K et al (2004) Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant 33:597–604PubMedCrossRefGoogle Scholar
  5. 5.
    Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP (1968) Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6:230–247PubMedCrossRefGoogle Scholar
  6. 6.
    Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317PubMedCrossRefGoogle Scholar
  7. 7.
    Bernardo ME, Locatelli F, Fibbe WE (2009) Mesenchymal stromal cells. Ann N Y Acad Sci 1176:101–117PubMedCrossRefGoogle Scholar
  8. 8.
    Devine SM, Cobbs C, Jennings M et al (2003) Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 101:2999–3001PubMedCrossRefGoogle Scholar
  9. 9.
    Hare JM, Traverse JH, Henry TD et al (2009) A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 54:2277–2286PubMedCrossRefGoogle Scholar
  10. 10.
    Hu SL, Luo HS, Li JT et al (2010) Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells. Crit Care Med 38:2181–2189PubMedCrossRefGoogle Scholar
  11. 11.
    Karussis D, Karageorgiou C, Vaknin-Dembinsky A et al (2010) Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 67:1187–1194PubMedCrossRefGoogle Scholar
  12. 12.
    Liang J, Zhang H, Hua B et al (2010) Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis 69:1423–1429PubMedCrossRefGoogle Scholar
  13. 13.
    Tolar J, Le Blanc K, Keating A, Blazar BR (2010) Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 28:1446–1455PubMedCrossRefGoogle Scholar
  14. 14.
    Caplan AI (2009) Why are MSCs therapeutic? New data: new insight. J Pathol 217:318–324PubMedCrossRefGoogle Scholar
  15. 15.
    Friedenstein AJ, Deriglasova UF, Kulagina NN et al (1974) Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 2:83–92PubMedGoogle Scholar
  16. 16.
    Nakahara H, Goldberg VM, Caplan AI (1991) Culture-expanded human periosteal-derived cells exhibit osteochondral potential in vivo. J Orthop Res 9:465–476PubMedCrossRefGoogle Scholar
  17. 17.
    Lee JY, Qu-Petersen Z, Cao B et al (2000) Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. J Cell Biol 150:1085–1100PubMedCrossRefGoogle Scholar
  18. 18.
    Arai F, Ohneda O, Miyamoto T et al (2002) Mesenchymal stem cells in perichondrium express activated leukocyte cell adhesion molecule and participate in bone marrow formation. J Exp Med 195:1549–1563PubMedCrossRefGoogle Scholar
  19. 19.
    Zuk PA, Zhu M, Mizuno H et al (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7:211–228PubMedCrossRefGoogle Scholar
  20. 20.
    Campagnoli C, Roberts IA, Kumar S et al (2001) Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98:2396–2402PubMedCrossRefGoogle Scholar
  21. 21.
    In ’t Anker PS, Noort WA, Scherjon SA et al (2003) Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica 88:845–852PubMedGoogle Scholar
  22. 22.
    In ’t Anker PS, Scherjon SA, Kleijburg-van der Keur C et al (2003) Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 102:1548–1549PubMedCrossRefGoogle Scholar
  23. 23.
    Miao Z, Jin J, Chen L et al (2006) Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell Biol Int 30:681–687PubMedCrossRefGoogle Scholar
  24. 24.
    Lee OK, Kuo TK, Chen WM et al (2004) Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 103:1669–1675PubMedCrossRefGoogle Scholar
  25. 25.
    Caplan AI (2007) Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 213:341–347PubMedCrossRefGoogle Scholar
  26. 26.
    Caimi PF, Reese J, Lee Z, Lazarus HM (2010) Emerging therapeutic approaches for multipotent mesenchymal stromal cells. Curr Opin Hematol 17:505–513PubMedCrossRefGoogle Scholar
  27. 27.
    Horwitz EM, Le Blanc K, Dominici M et al (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7:393–395PubMedCrossRefGoogle Scholar
  28. 28.
    Rasmusson I, Ringden O, Sundberg B, Le Blanc K (2005) Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 305:33–41PubMedCrossRefGoogle Scholar
  29. 29.
    Le Blanc K, Tammik L, Sundberg B et al (2003) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20PubMedCrossRefGoogle Scholar
  30. 30.
    Ren G, Zhang L, Zhao X et al (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2:141–150PubMedCrossRefGoogle Scholar
  31. 31.
    Polchert D, Sobinsky J, Douglas G et al (2008) IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 38:1745–1755PubMedCrossRefGoogle Scholar
  32. 32.
    Krampera M, Glennie S, Dyson J et al (2003) Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101:3722–3729PubMedCrossRefGoogle Scholar
  33. 33.
    Jiang XX, Zhang Y, Liu B et al (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105:4120–4126PubMedCrossRefGoogle Scholar
  34. 34.
    Nauta AJ, Kruisselbrink AB, Lurvink E et al (2006) Mesenchymal stem cells inhibit generation and function of both CD34+−derived and monocyte-derived dendritic cells. J Immunol 177:2080–2087PubMedGoogle Scholar
  35. 35.
    Zhang B, Liu R, Shi D et al (2009) Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population. Blood 113:46–57PubMedCrossRefGoogle Scholar
  36. 36.
    Spaggiari GM, Capobianco A, Abdelrazik H et al (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111:1327–1333PubMedCrossRefGoogle Scholar
  37. 37.
    Asari S, Itakura S, Ferreri K et al (2009) Mesenchymal stem cells suppress B-cell terminal differentiation. Exp Hematol 37:604–615PubMedCrossRefGoogle Scholar
  38. 38.
    Corcione A, Benvenuto F, Ferretti E et al (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107:367–372PubMedCrossRefGoogle Scholar
  39. 39.
    Chabannes D, Hill M, Merieau E et al (2007) A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood 110:3691–3694PubMedCrossRefGoogle Scholar
  40. 40.
    Sundin M, Barrett AJ, Ringden O et al (2009) HSCT recipients have specific tolerance to MSC but not to the MSC donor. J Immunother 32:755–764PubMedCrossRefGoogle Scholar
  41. 41.
    Majumdar MK, Keane-Moore M, Buyaner D et al (2003) Characterization and functionality of cell surface molecules on human mesenchymal stem cells. J Biomed Sci 10:228–241PubMedCrossRefGoogle Scholar
  42. 42.
    Le Blanc K, Tammik C, Rosendahl K et al (2003) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31:890–896PubMedCrossRefGoogle Scholar
  43. 43.
    Chan JL, Tang KC, Patel AP et al (2006) Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood 107:4817–4824PubMedCrossRefGoogle Scholar
  44. 44.
    Parekkadan B, Milwid JM (2010) Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng 12:87–117PubMedCrossRefGoogle Scholar
  45. 45.
    English K, Ryan JM, Tobin L et al (2009) Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(high) forkhead box P3+ regulatory T cells. Clin Exp Immunol 156:149–160PubMedCrossRefGoogle Scholar
  46. 46.
    Klyushnenkova E, Mosca JD, Zernetkina V et al (2005) T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 12:47–57PubMedCrossRefGoogle Scholar
  47. 47.
    Le Blanc K, Ringden O (2007) Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 262:509–525PubMedCrossRefGoogle Scholar
  48. 48.
    Cohen JL, Sudres M (2009) A role for mesenchymal stem cells in the control of ­graft-versus-host disease. Transplantation 87:S53–S54PubMedCrossRefGoogle Scholar
  49. 49.
    Lazarus HM, Haynesworth SE, Gerson SL et al (1995) Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant 16:557–564PubMedGoogle Scholar
  50. 50.
    Koc ON, Gerson SL, Cooper BW et al (2000) Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 18:307–316PubMedGoogle Scholar
  51. 51.
    Frassoni F, Labopin M, Bacigalupo A et al (2002) Expanded mesenchymal stem cells (MSC) co-infused with HLA identical stem cell transplants, reduce acute and chronic graft versus host disease: a matched pair analysis. Bone Marrow Transplant 29:S2Google Scholar
  52. 52.
    Le Blanc K, Samuelsson H, Gustafsson B et al (2007) Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia 21:1733–1738PubMedCrossRefGoogle Scholar
  53. 53.
    Ball LM, Bernardo ME, Roelofs H et al (2007) Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 110:2764–2767PubMedCrossRefGoogle Scholar
  54. 54.
    Macmillan ML, Blazar BR, DeFor TE, Wagner JE (2009) Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a phase I–II clinical trial. Bone Marrow Transplant 43:447–454PubMedCrossRefGoogle Scholar
  55. 55.
    Bernardo ME, Ball LM, Cometa AM et al (2011) Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation. Bone Marrow Transplant 46:200–207PubMedCrossRefGoogle Scholar
  56. 56.
    Gonzalo-Daganzo R, Regidor C, Martin-Donaire T et al (2009) Results of a pilot study on the use of third-party donor mesenchymal stromal cells in cord blood transplantation in adults. Cytotherapy 11:278–288PubMedCrossRefGoogle Scholar
  57. 57.
    Baron F, Lechanteur C, Willems E et al (2010) Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biol Blood Marrow Transplant 16:838–847PubMedCrossRefGoogle Scholar
  58. 58.
    Schriber J, Agovi MA, Ho V et al (2010) Second unrelated donor hematopoietic cell transplantation for primary graft failure. Biol Blood Marrow Transplant 16:1099–1106PubMedCrossRefGoogle Scholar
  59. 59.
    Fouillard L, Chapel A, Bories D et al (2007) Infusion of allogeneic-related HLA mismatched mesenchymal stem cells for the treatment of incomplete engraftment following autologous haematopoietic stem cell transplantation. Leukemia 21:568–570PubMedCrossRefGoogle Scholar
  60. 60.
    Fang B, Li N, Song Y et al (2009) Cotransplantation of haploidentical mesenchymal stem cells to enhance engraftment of hematopoietic stem cells and to reduce the risk of graft failure in two children with severe aplastic anemia. Pediatr Transplant 13:499–502PubMedCrossRefGoogle Scholar
  61. 61.
    Fang B, Song Y, Liao L et al (2007) Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 39:3358–3362PubMedCrossRefGoogle Scholar
  62. 62.
    Fang B, Song Y, Zhao RC et al (2007) Using human adipose tissue-derived mesenchymal stem cells as salvage therapy for hepatic graft-versus-host disease resembling acute hepatitis. Transplant Proc 39:1710–1713PubMedCrossRefGoogle Scholar
  63. 63.
    Meuleman N, Tondreau T, Ahmad I et al (2009) Infusion of mesenchymal stromal cells can aid hematopoietic recovery following allogeneic hematopoietic stem cell myeloablative transplant: a pilot study. Stem Cells Dev 18:1247–1252PubMedCrossRefGoogle Scholar
  64. 64.
    Sundin M, Orvell C, Rasmusson I et al (2006) Mesenchymal stem cells are susceptible to human herpesviruses, but viral DNA cannot be detected in the healthy seropositive individual. Bone Marrow Transplant 37:1051–1059PubMedCrossRefGoogle Scholar
  65. 65.
    Karlsson H, Samarasinghe S, Ball LM et al (2008) Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 112:532–541PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of MedicineUniversity Hospitals Case Medical Center, Case Comprehensive Cancer Center, Case Western Reserve UniversityClevelandUSA

Personalised recommendations