Download PDF
Transfusionsmedizin 2012; 2(1): 17-27
DOI: 10.1055/s-0031-1271598
Übersicht

© Georg Thieme Verlag KG Stuttgart ˙ New York

Mesenchymale Stromazellen und ihre klinische Anwendbarkeit

Mesenchymal Stromal Cells for Clinical ApplicationN. Fekete1 , M. Rojewski1 , G. Schmidtke-Schrezenmeier1 , H. Schrezenmeier1
  • 1Institut für Klinische Transfusionsmedizin und Immungenetik Ulm
    DRK Blutspendedienst Baden-Württemberg – Hessen und Institut für Transfusionsmedizin, Universität Ulm, Ulm
Further Information

Publication History

Publication Date:
17 February 2012 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Mesenchymale Stromazellen (MSC) sind fibroblastenähnliche Zellen, welche durch ihr Ver­halten in Zellkultur (Plastikadhärenz), ihr Expressionsmuster von Oberflächenantigenen sowie ihre zumindest trilineäre Differenzierungsfähigkeit (osteogen, chondrogen und adipozytär) definiert werden. Sie kommen beim Menschen in zahlreichen Geweben vor, und werden üblicherweise aus dem Knochenmark, dem Fettgewebe oder auch dem Nabelschnurblut isoliert und ex vivo expandiert. Dieser Weg über eine Ex-vivo-Expansionskultur ist notwendig, um eine ausreichende Anzahl an MSC, die als klinische Dosis zur Therapie benötigt wird, zu gewinnen. Für die möglichst kurz zu haltende Ex-vivo-Expansionsperiode sollten optimierte Kultursysteme und -protokolle sowie xenogenfreie Medien und Supplemente verwendet werden. Die immunmodulatorische Wirkung der MSC wurde bereits mehrfach erfolgreich in der Therapie der Transplantat-gegen-Wirt-Reaktion (GvHD) nach allogener Stammzelltransplantation nachgewiesen. Diese Erfahrungen veranlassten klinische Studien mit MSC bei anderen Erkrankungen mit einer Immunpathogenese, z. B. chronisch entzündliche Darmerkrankungen. Auch für die ­regenerative Behandlung von Gewebedefekten gibt es vielversprechende Daten aus In-vitro-Systemen und Tiermodellen. Die klinische Anwendung von MSC in diesen Indikationen (z. B. bei Myo­kardinfarkt, Knorpel- oder Knochendefekten) wird aktuell in einer Vielzahl von Studien geprüft. In diesem Beitrag fassen wir Aspekte zur Charakterisierung von MSC und der Ex-vivo-Expansion zusammen und ­geben eine Übersicht über aktuell durchgeführte klinische Prüfungen mit MSC. 

Schlüsselwörter

mesenchymale Stammzellen - mesenchymale Stromazellen - MSC - Ex-vivo-Expansion - zellbasierte Immuntherapie - Geweberegeneration - regenerative Therapie - Immunmodulation - Osteogenese - klinische Studien

Literatur

  • 1 Dominici M, Le Blanc K, Mueller I et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.  Cytotherapy. 2006;  8 315-317
    Google Scholar
  • 2 Rojewski M T, Weber B M, Schrezenmeier H. Phenotypic Characterization of Mesenchymal Stem Cells from Various Tissues.  Transfus Med Hemother. 2008;  35 168-184
    Google Scholar
  • 3 Guillot P V, Gotherstrom C, Chan J et al. Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.  Stem Cells. 2007;  25 646-654
    Google Scholar
  • 4 Kaiser S, Hackanson B, Follo M et al. BM cells giving rise to MSC in culture have a heterogeneous CD34 and CD45 phenotype.  Cytotherapy. 2007;  9 439-450
    Google Scholar
  • 5 da Silva Meirelles L, Chagastelles P C, Nardi N B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues.  J Cell Sci. 2006;  119 2204-2213
    Google Scholar
  • 6 Ye Z Q, Burkholder J K, Qiu P et al. Establishment of an adherent cell feeder layer from human umbilical cord blood for support of long-term hematopoietic progenitor cell growth.  Proc Natl Acad Sci USA. 1994;  91 12140-12144
    Google Scholar
  • 7 Crisan M, Yap S, Casteilla L et al. A perivascular origin for mesenchymal stem cells in multiple human organs.  Cell Stem Cell. 2008;  3 301-313
    Google Scholar
  • 8 Caplan A I. Mesenchymal stem cells.  J Orthop Res. 1991;  9 641-650
    Google Scholar
  • 9 Ahrens N, Tormin A, Paulus M et al. Mesenchymal Stem Cell Content of Human Vertebral Bone Marrow.  Transplantation. 2004;  78 925-929
    Google Scholar
  • 10 Wexler S A, Donaldson C, Denning-Kendall P et al. Adult bone marrow is a rich source of human mesenchymal ‘stem’ cells but umbilical cord and mobilized adult blood are not.  Br J Haematol. 2003;  121 368-374
    Google Scholar
  • 11 Lee R H, Kim B, Choi I et al. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue.  Cell Physiol Biochem. 2004;  14 311-324
    Google Scholar
  • 12 Lee O K, Kuo T K, Chen W M et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood.  Blood. 2004;  103 1669-1675
    Google Scholar
  • 13 Schallmoser K, Rohde E, Reinisch A et al. Rapid large-scale expansion of functional mesenchymal stem cells from unmanipulated bone marrow without animal serum.  Tissue Eng Part C Methods. 2008;  14 185-196
    Google Scholar
  • 14 Bartmann C, Rohde E, Schallmoser K et al. Two steps to functional mesenchymal stromal cells for clinical application.  Transfusion. 2007;  47 1426-1435
    Google Scholar
  • 15 Ruster B, Gottig S, Ludwig R J et al. Mesenchymal stem cells display coordinated rolling and adhesion be­havior on endothelial cells.  Blood. 2006;  108 3938-3944
    Google Scholar
  • 16 Yagi H, Soto-Gutierrez A, Parekkadan B et al. Mesenchymal stem cells: Mechanisms of immunomodulation and homing.  Cell Transplant. 2010;  19 667-679
    Google Scholar
  • 17 Lee R H, Pulin A A, Seo M J et al. Intravenous hMSCs Improve Myocardial Infarction in Mice because Cells ­Embolized in Lung Are Activated to Secrete the Anti-inflammatory Protein TSG-6.  Cell Stem Cell. 2009;  5 54-63
    Google Scholar
  • 18 Chamberlain G, Fox J, Ashton B et al. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing.  Stem Cells. 2007;  25 2739-2749
    Google Scholar
  • 19 Iso Y, Spees J L, Serrano C et al. Multipotent human stromal cells improve cardiac function after myocardial infarction in mice without long-term engraftment.  BiochemBiophysResCommun. 2007;  354 700-706
    Google Scholar
  • 20 Horwitz E M, Dominici M. How do mesenchymal stromal cells exert their therapeutic benefit?.  Cytotherapy. 2008;  10 771-774
    Google Scholar
  • 21 Commission Directive 2009 / 120 / EC of 14. September 2009 amending Directive 2001 / 83 / EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products.  Official Journal of the European Union. 2009;  52 3-12
    Google Scholar
  • 22 Schmidtke-Schrezenmeier G, Urban M, Musyanovych A et al. Labeling of mesenchymal stromal cells with iron oxide-poly(l-lactide) nanoparticles for magnetic resonance imaging: uptake, persistence, effects on cellular function and magnetic resonance imaging properties.  Cytotherapy. 2011;  [Epub ahead of print] 1-14
    Google Scholar
  • 23 Sensebe L, Krampera M, Schrezenmeier H et al. Mesenchymal stem cells for clinical application.  Vox Sang. 2010;  98 93-107
    Google Scholar
  • 24 Gieseke F, Böhringer J, Bussolari R et al. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells.  Blood. 2010;  116 3770-3779
    Google Scholar
  • 25 Waterman R S, Tomchuck S L, Henkle S L et al. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype.  PLoSOne. 2010;  5 e10088
    Google Scholar
  • 26 Tokoyoda K, Zehentmeier S, Hegazy A N et al. Professional memory CD4+ T lymphocytes preferentially ­reside and rest in the bone marrow.  Immunity. 2009;  30 721-730
    Google Scholar
  • 27 Klopp A H, Gupta A, Spaeth E et al. Concise review: Dissecting a discrepancy in the literature: do ­mesenchymal stem cells support or suppress tumor growth?.  Stem Cells;. 2011;  29 11-19
    Google Scholar
  • 28 Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease.  Nat Rev Immunol. 2008;  8 726-736
    Google Scholar
  • 29 Augello A, Kurth T B, De Bari C. Mesenchymal stem cells: a perspective from in vitro cultures to in vivo ­migration and niches.  Eur Cell Mater. 2010;  20 121-133
    Google Scholar
  • 30 Id B H, Lagneaux L, Najar M et al. The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts.  BMC Cancer. 2010;  10 298
    Google Scholar
  • 31 Mikami Y, Lee M, Irie S et al. Dexamethasone modulates osteogenesis and adipogenesis with regulation of osterix expression in rat calvaria-derived cells.  J Cell Physiol. 2011;  226 739-748
    Google Scholar
  • 32 Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche.  Cell Stem Cell. 2010;  7 150-161
    Google Scholar
  • 33 Schafer R, Northoff H. Characteristics of Mesenchymal Stem Cells – New Stars in Regenerative Medicine or Unrecognized Old Fellows in Autologous Regeneration?.  Transfus Med Hemother. 2008;  35 154-159
    Google Scholar
  • 34 Sato K, Ozaki K, Mori M et al. Mesenchymal Stromal Cells for Graft-Versus-Host Disease: Basic Aspects and Clinical Outcomes.  Journal of Clinical and Experimental Hematopathology. 2010;  50 79-89
    Google Scholar
  • 35 Sensebe L, Bourin P. Mesenchymal stem cells for therapeutic purposes.  Transplantation. 2009;  87 S49-S53
    Google Scholar
  • 36 Jethva R, Otsuru S, Dominici M et al. Cell therapy for disorders of bone.  Cytotherapy. 2009;  11 3-17
    Google Scholar
  • 37 Choi Y H, Kurtz A, Stamm C. Mesenchymal stem cells for cardiac cell therapy.  Hum Gene Ther. 2011;  22 3-17
    Google Scholar
  • 38 Aquino J B, Bolontrade M F, Garcia M G et al. Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma.  Gene Ther. 2010;  17 692-708
    Google Scholar
  • 39 Vija L, Farge D, Gautier J F et al. Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes.  Diabetes Metab. 2009;  35 85-93
    Google Scholar
  • 40 Duijvestein M, Vos A CW, Roelofs H et al. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn‘s disease: results of a phase I study.  Gut. 2010;  59 1662-1669
    Google Scholar
  • 41 Joyce N, Annett G, Wirthlin L et al. Mesenchymal stem cells for the treatment of neurodegenerative disease.  Regen Med. 2010;  5 933-946
    Google Scholar
  • 42 Le Blanc K, Rasmusson I, Sundberg B et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.  Lancet. 2004;  363 1439-1441
    Google Scholar
  • 43 Le Blanc K, Frassoni F, Ball L 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
    Google Scholar
  • 44 Fang B, Song Y, Liao L et al. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease.  Transplant Proc. 2007;  39 3358-3362
    Google Scholar
  • 45 Muller I, Kordowich S, Holzwarth C et al. Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation.  Blood Cells Mol Dis. 2008;  40 25-32
    Google Scholar
  • 46 Zhou H, Guo M, Bian C et al. Efficacy of bone marrow-derived mesenchymal stem cells in the treatment of sclerodermatous chronic graft-versus-host disease: clinical report.  Biol Blood Marrow Transplant. 2010;  16 403-412
    Google Scholar
  • 47 Ringden O, Uzunel M, Rasmusson I et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.  Transplantation. 2006;  81 1390-1397
    Google Scholar
  • 48 von Bonin M, Stolzel F, Goedecke A et al. Treatment of refractory acute GVHD with third-party MSC ­expanded in platelet lysate-containing medium.  Bone Marrow Transplant. 2008;  43 245-251
    Google Scholar
  • 49 Arima N, Nakamura F, Fukunaga A et al. Single intra-arterial injection of mesenchymal stromal cells for treatment of steroid-refractory acute graft-versus-host disease: a pilot study.  Cytotherapy. 2010;  12 265-268
    Google Scholar
  • 50 Allison M. Genzyme backs Osiris, despite Prochymal flop.  Nat Biotech. 2009;  27 966-967
    Google Scholar
  • 51 Osiris Therapeutics, Inc .Osiris Therapeutics Announces Preliminary Results for Prochymal Phase III GvHD Trials. 8.9.2009 Im Internet: http://http://www.osiristx.com/pdf/PR%20123%2008Sep09%20Phase%20III%20GvHD%20Topline%20Results.pdf Stand: 18.7.2011
    Google Scholar
  • 52 Rosland G V, Svendsen A, Torsvik A et al. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation.  Cancer Res. 2009;  69 5331-5339
    Google Scholar
  • 53 Rubio D, Garcia S, De la Cueva T et al. Human mesenchymal stem cell transformation is associated with a mesenchymal-epithelial transition.  Exp Cell Res. 2008;  314 691-698
    Google Scholar
  • 54 Rubio D, Garcia-Castro J, Martin M C et al. Spontaneous human adult stem cell transformation.  Cancer Res. 2005;  65 3035-3039
    Google Scholar
  • 55 Garcia S, Bernad A, Martin M C et al. Pitfalls in spontaneous in vitro transformation of human mesenchymal stem cells.  Exp Cell Res. 2010;  316 1648-1650
    Google Scholar
  • 56 de la Fuente R, Bernad A, Garcia-Castro J et al. Retraction: Spontaneous human adult stem cell transformation.  Cancer Res. 2010;  70 6682
    Google Scholar
  • 57 Torsvik A, Rosland G V, Svendsen A et al. Spontaneous malignant transformation of human mesenchymal stem cells reflects cross-contamination: putting the research field on track – letter.  Cancer Res. 2010;  70 6393-6396
    Google Scholar
  • 58 Tarte K, Gaillard J, Lataillade J J et al. Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation.  Blood. 2010;  115 1549-1553
    Google Scholar
  • 59 Klopp A H, Gupta A, Spaeth 3rd  E et al. Dissecting a Discrepancy in the Literature: Do Mesenchymal Stem Cells Support or Suppress Tumor Growth?.  Stem Cells. 2011;  29 11-19
    Google Scholar
  • 60 HEALTH-2009-1-4-2 .Regenerating Bone Defects Using New biomedical Engineering Approaches (RE­BORNE). Im Internet: http://http://www.reborne.org Stand: 18.7.2011
    Google Scholar
  • 61 HEALTH-F5-2009-223236 .Cultivated Adult Stem Cells as Alternative for Damaged Tissue (CASCADE) funded by the European Commissions 7th Framework Program. Im Internet: http://http://www.cascade-7fp.eu Stand: 18.7.2011
    Google Scholar
  • 62 Ning H, Yang F, Jiang M 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
    Google Scholar
  • 63 von Bonin M, Kiani A, Platzbecker U et al. Third-party mesenchymal stem cells as part of the management of graft-failure after haploidentical stem cell transplantation.  Leuk Res. 2009;  33 e215-e217
    Google Scholar
  • 64 Kebriaei P, Isola L, Bahceci E et al. Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease.  Biol Blood Marrow Transplant. 2009;  15 804-811
    Google Scholar
  • 65 Zhou H, Guo M, Bian C et al. Efficacy of Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Sclerodermatous Chronic Graft-versus-Host Disease: Clinical Report.  Biology of Blood and Marrow Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2010;  16 403-412
    Google Scholar

Prof. Dr. med. H. Schrezenmeier

Institut für Klinische Transfusions­medizin und Immungenetik Ulm

Helmholtzstraße 10

89081 Ulm

Email: h.schrezenmeier@blutspende.de

      >