Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Mesenchymal stromal cells: a novel and effective strategy for facilitating engraftment and accelerating hematopoietic recovery after transplantation?

Bone Marrow Transplantation volume 47, pages 323–329 (2012)Cite this article

Abstract

MSCs are multipotent cells that can be isolated from several human tissues and expanded ex vivo for clinical use. They comprise a heterogeneous population of cells, which, through production of growth factors, cell-to-cell interactions and secretion of matrix proteins, has a role in the regulation of hematopoiesis. In recent years, several experimental studies have shown that MSCs are endowed with immunomodulatory properties and with the capacity to promote graft survival in animal models. In view of these properties, MSCs have been tested in pilot studies aimed at preventing/treating graft rejection and at accelerating recovery after hematopoietic cell transplantation (HCT). The available clinical evidence deriving from these studies indicates that MSC infusion is safe and promising in terms of capacity of preventing graft failure. More debated is the effect of MSCs for what concerns their capacity of accelerating hematopoietic reconstitution after HCT. Whether the favorable effect of MSCs largely depends on the type of transplantation remains also a field of future investigation. Moreover, future researches should be oriented to gain more insights on MSC biological and functional mechanisms relevant for exploiting their use in the modulation of alloreactivity and in the promotion of hematopoietic reconstitution.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP . Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968; 6: 230–247.

    Article  CAS  Google Scholar 

  2. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 2005; 7: 393–395.

    Article  CAS  Google Scholar 

  3. Muller-Sieburg CE, Deryugina E . The stromal cells’ guide to the stem cell universe. Stem Cells 1995; 13: 477–486.

    Article  CAS  Google Scholar 

  4. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003; 425: 836–841.

    Article  CAS  Google Scholar 

  5. Haynesworth SE, Baber MA, Caplan AI . Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol 1996; 166: 585–592.

    Article  CAS  Google Scholar 

  6. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.

    Article  CAS  Google Scholar 

  7. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 2005; 7: 393–395.

    Article  CAS  Google Scholar 

  8. Anjos-Afonso F, Bonnet D . Nonhematopoietic/endothelial SSEA-1+ cells define the most primitive progenitors in the adult murine bone marrow mesenchymal compartment. Blood 2007; 109: 1298–1306.

    Article  CAS  Google Scholar 

  9. Gang EJ, Bosnakovski D, Figueiredo CA, Visser JW, Perlingeiro CR . SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood 2007; 109: 1743–1751.

    Article  CAS  Google Scholar 

  10. Simmons PJ, Torok-Storb B . Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood 1991; 78: 55–62.

    CAS  PubMed  Google Scholar 

  11. Buhring HJ, Battula VL, Treml S, Schewe B, Kanz I, Vogel W . Novel markers for the prospective isolation of human MSC. Ann N Y Acad Sci 2007; 1106: 262–271.

    Article  Google Scholar 

  12. Battula VL, Treml S, Bareiss PM, Gieseke F, Roelofs H, de Zwart P et al. Isolation of functionally distinct mesenchymal stem cells subsets using antibodies against CD56, CD271, and mesenchymal stem cell antigen-1 (MSCA-1). Haematologica 2009; 94: 173–184.

    Article  CAS  Google Scholar 

  13. Kuci S, Kuci Z, Kreyenberg H, Deak E, Putsch K, Huenecke S et al. CD271 antigen defines a subset of multipotent stromal cells with immunosuppressive and lymphohematopoietic engraftment-promoting properties. Haematologica 2010; 95: 651–659.

    Article  CAS  Google Scholar 

  14. Gronthos S, McCarty R, Mrozik K, Fitter S, Paton S, Menicanin D et al. Heat shock protein-90 beta is expressed at the surface of multipotential mesenchymal precursor cells: generation of a novel monoclonal antibody, STRO-4, with specificity for mesenchymal precursor cells from human an ovine tissues. Stem Cells Dev 2009; 18: 1253–1262.

    Article  CAS  Google Scholar 

  15. Ball LM, Bernardo ME, Roelofs H, Lankester A, Cometa A, Egeler RM et al. Co-transplantation 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 2007; 110: 2764–2767.

    Article  CAS  Google Scholar 

  16. Bernardo ME, Ball LM, Cometa AM, Roelofs H, Zecca M, Avanzini MA et al. Co-infusion of ex vivo expanded, parental mesenchymal stromal cells 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 2011; 46: 200–207.

    Article  CAS  Google Scholar 

  17. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371: 1579–1586.

    Article  CAS  Google Scholar 

  18. Spees JL, Gregory CA, Singh H, Tucker HA, Peister A, Lynch PJ et al. Internalized antigens must be removed to prepare hypoimmunogenic mesenchymal stem cells for cell and gene therapy. Mol Ther 2004; 9: 747–756.

    Article  CAS  Google Scholar 

  19. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999; 5: 309–313.

    Article  CAS  Google Scholar 

  20. Shahdadfar A, Fronsdal K, Haug T, Reinholt FP, Brinchmann JE . In vitro expansion of human mesenchymal stem cells: choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptosome stability. Stem Cells 2005; 23: 1357–1366.

    Article  CAS  Google Scholar 

  21. Jung S, Sen A, Rosenberg L, Behie LA . Identification of growth and attachment factors for the serum-free isolation and expansion of human mesenchymal stromal cells. Cytotherapy 2010; 12: 637–657.

    Article  CAS  Google Scholar 

  22. Chase LG, Lakshmipathy U, Solchaga LA, Rao MS, Vemuri MC . A novel serum-free medium for the expansion of human mesenchymal stem cells. Stem Cell Res Ther 2010; 1: 8–11.

    Article  Google Scholar 

  23. Doucet C, Ernou I, Zhang Y, Llense JR, Begot L, Holy X et al. Platelet lysates promote mesenchymal stem cell expansion: a safety substitute for animal serum in cell-based therapy applications. J Cell Physiol 2005; 205: 228–236.

    Article  CAS  Google Scholar 

  24. Bernardo ME, Avanzini MA, Perotti C, Cometa AM, Moretta A, Lenta E et al. Optimization of in vitro expansion of human multipotent mesenchymal stromal cells for cell-therapy approaches: further insights in the search for a fetal calf serum substitute. J Cell Physiol 2007; 211: 121–130.

    Article  CAS  Google Scholar 

  25. Schallmoser K, Bartmann C, Rohde E, Reinisch A, Kashofer K, Stadelmeyer E et al. Human platelet lysate can replace fetal bovine serum for clinical-scale expansion of functional mesenchymal stromal cells. Transfusion 2007; 47: 1436–1446.

    Article  CAS  Google Scholar 

  26. Nauta AJ, Fibbe WE . Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110: 3499–3506.

    Article  CAS  Google Scholar 

  27. Locatelli F, Maccario R, Frassoni F . Mesenchymal stromal cells, from indifferent spectators to principal actors. Are we going to witness a revolution in the scenario of allograft and immune-mediated disorders? Haematologica 2007; 92: 872–877.

    Article  Google Scholar 

  28. Uccelli A, Pistoia V, Moretta L . Mesenchymal stem cells: a new strategy for immunosuppression? Trends Immunol 2007; 28: 219–226.

    Article  CAS  Google Scholar 

  29. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or non specific mitogenic stimuli. Blood 2002; 99: 3838–3843.

    Article  CAS  Google Scholar 

  30. Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte derived dendritic cells. Blood 2005; 105: 4120–4126.

    Article  CAS  Google Scholar 

  31. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE . Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 2006; 177: 2080–2087.

    Article  CAS  Google Scholar 

  32. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L . Mesenchymal stem cell–natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 2006; 107: 1484–1490.

    Article  CAS  Google Scholar 

  33. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F et al. Human mesenchymal stem cells modulate B cell functions. Blood 2006; 107: 367–372.

    Article  CAS  Google Scholar 

  34. Traggiai E, Volpi S, Schena F, Gattorno M, Ferlito F, Moretta L et al. Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients. Stem Cells 2008; 26: 562–569.

    Article  CAS  Google Scholar 

  35. Almeida-Porada G, Porada CD, Tran N, Zanjani ED . Co-transplantation of human stromal cell progenitors into pre-immune fetal sheep results in early appearance of human donor cells in circulation and boosts cell levels in bone marrow at later time points after transplantation. Blood 2000; 95: 3620–3627.

    CAS  PubMed  Google Scholar 

  36. Noort WA, Kruisselbrink AB, in’t Anker PS, Kruger M, van Bezooijen RL, de Paus RA et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34+ cells in NOD/SCID mice. Exp Hematol 2002; 30: 870–878.

    Article  Google Scholar 

  37. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002; 30: 42–48.

    Article  Google Scholar 

  38. Hiwase SD, Dyson PG, To LB, Lewis ID . Cotransplantation of placental mesenchymal stromal cells enhances single and double cord engraftment in nonobese diabetic/severe immune deficient mice. Stem Cells 2009; 27: 2293–2300.

    Article  Google Scholar 

  39. Masuda S, Ageyama N, Shibata H, Obara Y, Ikeda T, Takeuchi K et al. Cotransplantation with MSCs improves engraftment of HSCs after autologous intra-bone marrow transplantation in nonhuman primates. Exp Hematol 2009; 37: 1250–1257.

    Article  CAS  Google Scholar 

  40. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE . Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a non-myeloablative setting. Blood 2006; 108: 2114–2120.

    Article  CAS  Google Scholar 

  41. Devine SM, Bartholomew AM, Mahmud N, Nelson M, Patil S, Hardy W et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 2001; 29: 244–255.

    Article  CAS  Google Scholar 

  42. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI . The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001; 169: 12–20.

    Article  CAS  Google Scholar 

  43. Wynn RF, Hart CA, Corradi-Perini C, O’Neill L, Evans CA, Wraith JE et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood 2004; 104: 2643–2645.

    Article  CAS  Google Scholar 

  44. Sackstein R, Merzaban JS, Cain DW, Dagia NM, Spencer JA, Lin CP et al. Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med 2008; 14: 181–187.

    Article  CAS  Google Scholar 

  45. Schäfer R, Kehlbach R, Müller M, Bantleon R, Kluba T, Ayturan M et al. Labeling of human mesenchymal stromal cells with superparamagnetic iron oxide leads to a decrease in migration capacity and colony formation ability. Cytotherapy 2009; 11: 68–78.

    Article  Google Scholar 

  46. Schäfer R, Ayturan M, Bantleon R, Kehlbach R, Siegel G, Pintaske J et al. The use of clinically approved small particles of iron oxide (SPIO) for labeling of mesenchymal stem cells aggravates clinical symptoms in experimental autoimmune encephalomyelitis and influences their in vivo distribution. Cell Transplant 2008; 17: 923–941.

    Article  Google Scholar 

  47. Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI et al. Rapid hematopoietic recovery after co-infusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000; 18: 307–316.

    Article  CAS  Google Scholar 

  48. Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 2005; 11: 389–398.

    Article  Google Scholar 

  49. Kim DW, Chung YJ, Kim TG, Kim YL, Oh IH . Cotransplantation of third-party mesenchymal stromal cells can alleviate single-donor predominance and increase engraftment from double cord transplantation. Blood 2004; 103: 1941–1948.

    Article  CAS  Google Scholar 

  50. MacMillan ML, Blazar BR, DeFor TE, Wagner JE . Transplantation of culture-expanded 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 2008; 43: 1–8.

    Google Scholar 

  51. Gonzalo-Daganzo R, Regidor C, Martìn-Donaire T, Rico MA, Bautista G, Krsnik I et al. Results of a pilot study on the use of third-party mesenchymal stromal cells in cord blood transplantation in adults. Cytotherapy 2009; 11: 278–288.

    Article  CAS  Google Scholar 

  52. Awaya N, Rupert K, Bryant E, Torok-Storb B . Failure of adult marrow-derived stem cells to generate marrow stroma after successful hematopoietic stem cell transplantation. Exp Hematol 2002; 30: 937–942.

    Article  Google Scholar 

  53. Rieger K, Marinets O, Fietz T, Körper S, Sommer D, Mücke C et al. Mesenchymal stem cells remain of host origin even a long time after allogeneic peripheral blood stem cell or bone marrow transplantation. Exp Hematol 2005; 33: 605–611.

    Article  CAS  Google Scholar 

  54. Koc ON, Peters C, Aubourg P, Raghavan S, Dyhouse S, DeGasperi R et al. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp Hematol 1999; 27: 1675–1681.

    Article  CAS  Google Scholar 

  55. Cilloni D, Carlo-Stella C, Falzetti F, Sammarelli G, Regazzi E, Colla S et al. Limited engraftment capacity of bone marrow-derived mesenchymal cells following T-cell-depleted hematopoietic stem cell transplantation. Blood 2000; 96: 3637–3643.

    CAS  PubMed  Google Scholar 

  56. Pozzi S, Lisini D, Podestà M, Bernardo ME, Sessarego N, Piaggio G et al. Donor multipotent mesenchymal stromal cells may engraft in pediatric patients given either cord blood or bone marrow transplantation. Exp Hematol 2006; 34: 934–942.

    Article  CAS  Google Scholar 

  57. Robinson SN, Ng J, Niu T, Yang H, McCannis JD, Karandish S et al. Superior ex vivo expansion cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells. Bone Marrow Transpl 2006; 37: 359–366.

    Article  CAS  Google Scholar 

  58. Tung SS, Parmar S, Robinson SN, De Lima M, Shpall EJ . Ex vivo expansion of umbilical cord blood for transplantation. Bets Practice Res Clin Hematol 2010; 23: 245–257.

    Article  CAS  Google Scholar 

  59. Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003; 102: 3837–3844.

    Article  CAS  Google Scholar 

  60. Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia 2008; 22: 593–599.

    Article  CAS  Google Scholar 

  61. Karlsson H, Samarasinghe S, Ball LM, Sundberg B, Lankester AC, Dazzi F et al. Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 2008; 112: 532–541.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work has been partly supported by grants from Istituto Superiore di Sanità (National Program on Stem Cells), MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca, Progetti di Rilevante Interesse Nazionale, PRIN), from Associazione Italiana per la Ricerca sul Cancro (AIRC) IG9062 to MEB and by the special grant ‘5 × 1000’ from AIRC to FL.

Author information

Authors and Affiliations

  1. Dipartimento di Ematologia ed Oncologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy

    M E Bernardo, A M Cometa & F Locatelli

  2. Università degli Studi di Pavia, Pavia, Italy

    F Locatelli

Authors
  1. M E Bernardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A M Cometa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Locatelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M E Bernardo.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernardo, M., Cometa, A. & Locatelli, F. Mesenchymal stromal cells: a novel and effective strategy for facilitating engraftment and accelerating hematopoietic recovery after transplantation?. Bone Marrow Transplant 47, 323–329 (2012). https://doi.org/10.1038/bmt.2011.102

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2011.102

Keywords

This article is cited by

Search

Advanced search

Quick links