Abstract
Mesenchymal stromal cells (MSCs) can be isolated from several human tissues and expanded for clinical use. MSCs are identified by phenotypic and functional characteristics, and are poor Ag-presenting cells not expressing MHC class II or co-stimulatory molecules. MSCs have potent immune-modulatory effects and in vitro induce a more anti-inflammatory or tolerant phenotype. Clinical studies have exploited both the immune-modulatory properties of MSCs as well as their hematopoietic supportive role. MSCs have been safely administered for the treatment of severe steroid refractory GVHD. A phase I/II multicenter study included 25 children in whom 80% responded to either one or two infusions of MSCs derived mainly from third party donors. Twenty children have undergone co-transplantation of haploidentical MSCs with PBSC in a phase I/II study, which has overcome the problems of graft failure in HLA-disparate grafts. Similarly, co-transplantation of MSCs and cord blood stem cells is under investigation. MSCs may have important future potential for the treatment of pediatric autoimmune disease as well as inborn errors such as osteogenesis imperfecta. Currently, much needed randomized studies under the auspices of the EBMT are ongoing to determine the optimal use of these exciting new modalities of treatment.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fibbe WE, Lazarus HM . Mesenchynmal stem cells and hematopoietic stem cell transplantation. In: Atkinson K, Champlin R, Brenner MA, Fibbe WE, Ritz J, Ljungman P (eds), 3rd edn. Clinical Bone Marrow and Blood Stem Cell Transplantation. Cambridge University Press, UK, 2004, pp 67–78.
Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Ruadkow IA . Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 1974; 2: 83–92.
Owen M . Marrow stromal stem cells. J Cell Sci 1988; 10 (Suppl): 63–76.
Prockop DJ . Marrow stromal cells as stem cells for non-hematopoietic tissues. Science 1997; 276: 71–74.
Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL . Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol 1998; 176: 57–66.
Almeida-Porada G, Flake AW, Glimp HA, Zanjani ED . Cotransplantation of stroma results in enhancement of engraftment and early expression of donor hematopoietic stem cells in utero. Exp Hematol 1999; 27: 1569–1575.
In ‘t Anker PS, Noort WA, Kruisselbrink AB, Scherjon SA, Beekhuizen W, Willemze R et al. Non expanded primary lung and bone marrow-derived mesenchymal cells promote the engraftment of umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol 2003; 31: 881–889.
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.
Nathanson MA . Bone matrix-directed chondrogenesis of muscle in vitro. Clin Orthop 1985; 200: 142–158.
Nakahara H, Dennis JE, Bruder SP, Haynesworth SE, Lennon DP, Caplan AI . In vitro differentiation of bone and hypertrophic cartilage from periosteal-derived cells. Exp Cell Res 1991; 195: 492–503.
Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM . Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001; 98: 2396–2402.
Fernandez M, Simon V, Herrera G, Cao C, Del Favero H, Minguell JJ . Detection of stromal cells in peripheral blood progenitor cell collections from breast cancer patients. Bone Marrow Transplant 1997; 20: 265–271.
Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI . Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant 1995; 16: 557–564.
Erices A, Conget P, Minguell JJ . Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000; 109: 235–242.
Mareschi K, Biasin E, Piacibello W, Aglietta M, Madon E, Fagioli F . Isolation of human mesenchymal stem cells: bone marrow versus umbilical cord blood. Haematologica 2001; 86: 1099–1100.
In ‘t Anker PS, Scherjon SA, Kleijburg-Van Der Keur C, Noort WA, Claas FH, Willemze R et al. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 2003; 102: 1548–1549.
Battula VL, Treml S, Abele H, Bühring HJ . Prospective isolation and characterization of mesenchymal stem cells from human placenta using a frizzled-9-specific monoclonal antibody. Differentiation 2008; 76: 326–336.
Banfi A, Bianchi G, Notaro R, Luzzatto L, Cancedda R, Quarto R . Replicative aging and gene expression in long-term cultures of human bone marrow stromal cells. Tissue Eng 2002; 8: 901–910.
Vogel JP, Szalay K, Geiger F, Kramer M, Richter W, Kasten P . Platelet-rich plasma improves expansion of human mesenchymal stem cells and retains differentiation capacity and in vivo bone formation in calcium phosphate ceramics. Platelets 2006; 17: 462–469.
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 nonspecific mitogenic stimuli. Blood 2002; 99: 3838–3843.
Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F . Bone marrow mesenchymal stem cells inhibit the response of naïve and memory antigen-specific T-cells to their cognate peptide. Blood 2004; 101: 3722–3729.
Aggarwal S, Pittenger MF . Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815–1822.
Sotiropoulou PA, Perz SA, Gritzapis AD, Baxevanis CN, Papmichail M . Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24: 74–85.
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 nonmyeloablative setting. Blood 2006; 108: 2114–2120.
Nauta AJ, Fibbe WE . Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110: 3499–3506.
Meisel R, Ziber A, Laryea M, Göbel U, Däubener W, Dilloo D . Human bone marrow stromal cells inhibit allogeneic responses by indoleamine 2,3 dioxygenase mediated tryptophan degradation. Blood 2004; 103: 4619–4621.
Rasmusson I, Ringden O, Sundberg B, Le Blanc K . Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 2003; 76: 1208–1213.
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.
Devine SM, Bartholomew AM, Mahmud N, Nelson M, Patil S, Hardy W, Sturgeon C 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.
Noort WA, Kruisselbrink AB, de Paus RA, Kruger M, van Bezooijen RL, de Paus RA et al. Co-transplantation of mesenchymal stem cells (MSCs) and UCB CD34+ cells results in enhanced hematopoietic engraftment in NOD/SCID mice without homing. Exp Hematol 2002; 30: 870–878.
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.
Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, RamÃrez M, Bueren JA . Adipose tissue-derived mesenchymal stem cells (AD-MSC) have in vivo immunosuppressive properties applicable for the control of graft-versus-host disease (GVHD). Stem Cells 2006; 24: 2582–2591.
Zhang J, Li Y, Chen J, Cui Y, Lu M, Elias SB et al. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 2005; 195: 16–26.
Djouad F, Fritz V, Apparailly F, Louis-Plence P, Bony C, Sany J et al. Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. Arthritis Rheum 2005; 52: 1595–1603.
Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, Lazarus HM . 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.
Lazarus HM, Curtin P, Devine S, 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.
Frassoni F, Labopin M, Bacigalupo A, Gluckman E, Rocha V, Bruno B et al. Expanded mesenchymal stem cells (MSCs), co-infused with HLA identical hemopoietic stem cell transplants, reduce acute and chronic graft versus host disease: a matched pair analysis. Bone Marrow Transplant 2002; 29 (Suppl 2): S2.
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.
Krivit W, Shapiro EG, Lockman LA, Koc ON, Lazarus HM . Bone marrow transplantation: treatment for globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy and Hurler syndrome. In: Moser HW, Vinken PJ, Bruyn GW (eds). Handbook of Clinical Neurology. Elsevier Science: Amsterdam, 1996, pp 87–106.
Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W . Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002; 30: 215–222.
Sillence DO, Rimoin DL, Danks DM . Clinical variability in osteogenesis imperfecta-variable expressivity or genetic heterogeneity. Birth Defects Orig Artic Ser 1979; 15: 113–129.
Horwitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA, Neel MD et al. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 2001; 97: 1227–1231.
Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci USA 2002; 99: 8932–8937.
Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F et al. Treatment of high risk acute leukemia with T-cell depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 998; 339: 1186–1193.
Handgretinger R, Lang P, Klingebiel T, Schumm M, Neu S, Geiselhart A et al. Megadose transplantation of purified peripheral blood CD34+ progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant 2001; 27: 777–831.
Passweg JR, Kuhne T, Gregor M, Favre G, Avoledo P, Tichelli A, Gratwohl A . Increased stem cell dose, as obtained using currently available technology, may not be sufficient for engraftment of haploidentical stem cell transplantation. Bone Marrow Transplant 2000; 26: 1033–1036.
Ball LM, Bernardo ME, Roleofs 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 haplo-identical hematopoietic stem cell transplantation. Blood 2007; 110: 2764–2767.
Broxmeyer HE . Introduction: The past, present and future of cord blood transplantation. In: Broxmeyer HE (ed). The Cellular Characteristics of Cord Blood and Cord Blood Transplantation. AABB press: Bethesda, Maryland, 1998, pp 1–9.
Gluckman E, Broxmeyer HE, Auerbach AD, Friedman HS, Douglas GW, Devergie A et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from and HLA-identical sibling. N Engl J Med 1989; 321: 1174–1178.
Barker JN, Wagner JE . Umbilical cord blood transplantation: current state of the art. Curr Opin Oncol 2002; 14: 160–164.
Barker JN, Krepski TP, DeFor TE, Davies SM, Wagner JE, Weisdorf DJ . Searching for unrelated donor hematopoietic stem cells availability and speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant 2002; 8: 257–260.
Gluckman E, Rocha V, Chevret S . Results of unrelated umbilical cord blood transplant. Transfus Clin Biol 2001; 8: 146–154.
Rocha V, Wagner JE, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM et al. Graft-versus-host disease in children who have received a cord blood or bone marrow transplant from an HLA-identical sibling. N Engl J Med 2000; 342: 1846–1854.
Locatelli F, Rocha V, Chastang C, Arcese W, Michel G, Abecasis M et al. Factors associated with outcome after cord blood transplantation in children with acute leukemia. Eurocord-Cord Blood Transplant Group. Blood 1999; 93: 3662–3671.
Rocha V, Cornish J, Sievers EL, Filipovich A, Locatelli F, Peters C et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. Blood 2001; 97: 2962–2971.
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.
Bernardo ME, Ball LM, Cometa AM, Zecca M, Giorgiani G, Maccario R et al. Co transplantation of parental mesenchymal stem cells to improve outcome of cord blood transplantation in children. Bone Marrow Transplant 2006; 37: S1.
Couriel A, Caldera H, Champlin R, Komanduri K . Acute graft versus host disease: pathophysiology, clinical manifestations, and management. Cancer 2004; 101: 1936–1946.
Deeg HJ . How I treat refractory acute GVHD. Blood 2007; 109: 4119–4126.
Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O . Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363: 1439–1441.
Le Blanc K, Frassoni F, Ball LM, Locatelli F, Roelofs H, Lewis I et al. Mesenchymal stem cells for treatment of severe, refractory acute graft-versus-host disease. Bone Marrow Transplant 2008; 41: S1–S215.
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.
Ringden O, Uzunel M, Sundberg B, Lönnies L, Nava S, Gustafsson J et al. Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 2007; 21: 2271–2276.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ball, L., Bernardo, M., Locatelli, F. et al. Potential role of mesenchymal stromal cells in pediatric hematopoietic SCT. Bone Marrow Transplant 42 (Suppl 2), S60–S66 (2008). https://doi.org/10.1038/bmt.2008.286
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2008.286
Keywords
This article is cited by
-
Autologous chondrocyte implantation in the knee is effective in skeletally immature patients: a systematic review
Knee Surgery, Sports Traumatology, Arthroscopy (2023)
-
Emerging uses for pediatric hematopoietic stem cells
Pediatric Research (2012)
-
Multiplex Analysis of Cytokines, Chemokines, Growth Factors, MMP-9 and TIMP-1 Produced by Human Bone Marrow, Adipose Tissue, and Placental Mesenchymal Stromal Cells
Bulletin of Experimental Biology and Medicine (2011)