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Future of cord blood for non-oncology uses

Abstract

For the last 5 years cord blood (CB) has been under intense experimental investigation in in vitro differentiation models and in preclinical animal models ranging from bone to muscle regeneration, cardiovascular diseases including myocardial and peripheral arterial disease, stroke and Parkinson's disease. On the basis of its biological advantages, CB can be an ideal source for tissue regeneration. However, in the hype of the so-called ‘plasticity’, many cell types have been characterized either on cell surface Ag expression alone or by RNA expression only, and without detailed characterization of genetic pathways; frequently, cells are defined without analysis of cellular function in vitro and in vivo, and the definition of the lineage of origin and cells have not been defined in preclinical studies. Here, we explore not only the most consistent data with regard to differentiation of CB cells in vitro and in vivo, but also show technical limitations, such as why in contrast to cell populations isolated from fresh CB, cryopreserved CB is not the ideal source for tissue regeneration. By taking advantage of numerous CB units discarded due to lack of sufficient hematopoietic cells for clinical transplantation, new concepts to produce off-the-shelf products are presented as well.

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References

  1. Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 2004; 200: 123–135.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kogler G, Radke TF, Lefort A, Sensken S, Fischer J, Sorg RV et al. Cytokine production and hematopoiesis supporting activity of cord blood-derived unrestricted somatic stem cells. Exp Hematol 2005; 33: 573–583.

    Article  PubMed  CAS  Google Scholar 

  3. Kogler G, Sensken S, Wernet P . Comparative generation and characterization of pluripotent unrestricted somatic stem cells with mesenchymal stem cells from human cord blood. Exp Hematol 2006; 34: 1589–1595.

    Article  PubMed  CAS  Google Scholar 

  4. Sensken S, Waclawczyk S, Knaupp AS, Trapp T, Enczmann J, Wernet P et al. In vitro differentiation of human cord blood-derived unrestricted somatic stem cells towards an endodermal pathway. Cytotherapy 2007; 9: 362–378.

    Article  CAS  PubMed  Google Scholar 

  5. Trapp T, Kogler G, El-Khattouti A, Sorg RV, Besselmann M, Focking M et al. Hepatocyte growth factor/c-MET axis-mediated tropism of cord blood-derived unrestricted somatic stem cells for neuronal injury. J Biol Chem 2008; 283: 32244–32253.

    Article  CAS  PubMed  Google Scholar 

  6. Greschat S, Schira J, Kury P, Rosenbaum C, de Souza Silva MA, Kogler G et al. Unrestricted somatic stem cells from human umbilical cord blood can be differentiated into neurons with a dopaminergic phenotype. Stem Cells Dev 2008; 17: 221–232.

    Article  CAS  PubMed  Google Scholar 

  7. Erices A, Conget P, Minguell JJ . Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000; 109: 235–242.

    Article  CAS  PubMed  Google Scholar 

  8. Bieback K, Kern S, Kluter H, Eichler H . Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 2004; 22: 625–634.

    Article  PubMed  Google Scholar 

  9. Yang SE, Ha CW, Jung M, Jin HJ, Lee M, Song H et al. Mesenchymal stem/progenitor cells developed in cultures from UC blood. Cytotherapy 2004; 6: 476–486.

    Article  PubMed  Google Scholar 

  10. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007; 109: 1801–1809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. McGuckin CP, Forraz N, Baradez MO, Navran S, Zhao J, Urban R et al. Production of stem cells with embryonic characteristics from human umbilical cord blood. Cell Prolif 2005; 38: 245–255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McGuckin C, Forraz N, Baradez MO, Basford C, Dichinson AM, Navran S et al. Embryonic-like stem cells from umbilical cord blood and potential for neural modeling. Acta Neurobiol Exp (Wars) 2006; 66: 321–329.

    Google Scholar 

  13. McGuckin CP, Forraz N . Potential for access to embryonic-like cells from human umbilical cord blood. Cell Prolif 2008; 41 (Suppl 1): 31–40.

    PubMed  Google Scholar 

  14. Liedtke S, Enczmann J, Waclawczyk S, Wernet P, Kogler G . Oct4 and its pseudogenes confuse stem cell research. Cell Stem Cell 2007; 1: 364–366.

    Article  CAS  PubMed  Google Scholar 

  15. Liedtke S, Stephan M, Kogler G . Oct4 expression revisited: potential pitfalls for data misinterpretation in stem cell research. Biol Chem 2008; 389: 845–850.

    Article  CAS  PubMed  Google Scholar 

  16. Kotoula V, Papamichos SI, Lambropoulos AF . Revisiting OCT4 expression in peripheral blood mononuclear cells. Stem Cells 2008; 26: 290–291.

    Article  CAS  PubMed  Google Scholar 

  17. Cantz T, Key G, Bleidissel M, Gentile L, Han DW, Brenne A et al. Absence of OCT4 expression in somatic tumor cell lines. Stem Cells 2008; 26: 692–697.

    Article  CAS  PubMed  Google Scholar 

  18. Buchheiser A, Looijenga LH, Liedtke S, Kogler G . Cord blood for tissue regeneration. J Cell Biochem 2009 (e-pub ahead of print 19711371).

  19. Houben A, Buchheiser A, Aktas M, Fischer J, Kogler G . Age-related differences btween unrestricted somatic stem cells from cord blood and bone marrow derived mesenchymal stroma cells. Blood 2008; 112: 481; abstract.

    Article  Google Scholar 

  20. Buchheiser A, Liedtke S, Houben A, Waclawczyk S, Stephan M, Radke T et al. Cord blood:a very valuable source of neonatal cells but embryonic nature reevaluated. Blood 2008; 112: 997; abstract.

    Article  Google Scholar 

  21. Honecker F, Kersemaekers AM, Molier M, Van Weeren PC, Stoop H, De Krijger RR et al. Involvement of E-cadherin and beta-catenin in germ cell tumours and in normal male fetal germ cell development. J Pathol 2004; 204: 167–174.

    Article  CAS  PubMed  Google Scholar 

  22. Stoop H, Honecker F, Cools M, de Krijger R, Bokemeyer C, Looijenga LH . Differentiation and development of human female germ cells during prenatal gonadogenesis: an immunohistochemical study. Hum Reprod 2005; 20: 1466–1476.

    Article  CAS  PubMed  Google Scholar 

  23. Oosterhuis JW, Stoop H, Honecker F, Looijenga LH . Why human extragonadal germ cell tumours occur in the midline of the body: old concepts, new perspectives. Int J Androl 2007; 30: 256–263; discussion 263–254.

    Article  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. Rosada C, Justesen J, Melsvik D, Ebbesen P, Kassem M . The human umbilical cord blood: a potential source for osteoblast progenitor cells. Calcif Tissue Int 2003; 72: 135–142.

    Article  CAS  PubMed  Google Scholar 

  26. Bieback K, Kern S, Kocaomer A, Ferlik K, Bugert P . Comparing mesenchymal stromal cells from different human tissues: bone marrow, adipose tissue and umbilical cord blood. Biomed Mater Eng 2008; 18: S71–S76.

    CAS  PubMed  Google Scholar 

  27. Gang EJ, Hong SH, Jeong JA, Hwang SH, Kim SW, Yang IH et al. In vitro mesengenic potential of human umbilical cord blood-derived mesenchymal stem cells. Biochem Biophys Res Commun 2004; 321: 102–108.

    Article  CAS  PubMed  Google Scholar 

  28. Charbord P, Oostendorp R, Pang W, Herault O, Noel F, Tsuji T et al. Comparative study of stromal cell lines derived from embryonic, fetal, and postnatal mouse blood-forming tissues. Exp Hematol 2002; 30: 1202–1210.

    Article  CAS  PubMed  Google Scholar 

  29. Goodwin HS, Bicknese AR, Chien SN, Bogucki BD, Quinn CO, Wall DA . Multilineage differentiation activity by cells isolated from umbilical cord blood: expression of bone, fat, and neural markers. Biol Blood Marrow Transplant 2001; 7: 581–588.

    Article  CAS  PubMed  Google Scholar 

  30. Kluth SM, Buchheiser A, Waclawczyk S, Krenz T, Bosch J, Houben AP et al. Functional differences correlate with the expression of DLK-1 and distinguish USSC from MSC in human cord blood. 2009 (in preparation).

  31. Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, Chen TH . Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004; 103: 1669–1675.

    Article  CAS  PubMed  Google Scholar 

  32. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964–967.

    Article  CAS  PubMed  Google Scholar 

  33. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89: E1–E7.

    Article  CAS  PubMed  Google Scholar 

  34. Ito H, Rovira II, Bloom ML, Takeda K, Ferrans VJ, Quyyumi AA et al. Endothelial progenitor cells as putative targets for angiostatin. Cancer Res 1999; 59: 5875–5877.

    CAS  PubMed  Google Scholar 

  35. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593–600.

    Article  PubMed  Google Scholar 

  36. Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 2000; 95: 952–958.

    Article  CAS  PubMed  Google Scholar 

  37. Rehman J, Li J, Orschell CM, March KL . Peripheral blood ‘endothelial progenitor cells’ are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107: 1164–1169.

    Article  PubMed  Google Scholar 

  38. Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK et al. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol 2004; 24: 288–293.

    Article  CAS  PubMed  Google Scholar 

  39. Sieveking DP, Buckle A, Celermajer DS, Ng MK . Strikingly different angiogenic properties of endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay. J Am Coll Cardiol 2008; 51: 660–668.

    Article  CAS  PubMed  Google Scholar 

  40. Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000; 97: 3422–3427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Timmermans F, Van Hauwermeiren F, De Smedt M, Raedt R, Plasschaert F, De Buyzere ML et al. Endothelial outgrowth cells are not derived from CD133+ cells or CD45+ hematopoietic precursors. Arterioscler Thromb Vasc Biol 2007; 27: 1572–1579.

    Article  CAS  PubMed  Google Scholar 

  42. Gunsilius E, Duba HC, Petzer AL, Kahler CM, Grunewald K, Stockhammer G et al. Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet 2000; 355: 1688–1691.

    Article  CAS  PubMed  Google Scholar 

  43. Hirschi KK, Ingram DA, Yoder MC . Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008; 28: 1584–1595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Asosingh K, Aldred MA, Vasanji A, Drazba J, Sharp J, Farver C et al. Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension. Am J Pathol 2008; 172: 615–627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yoon CH, Hur J, Park KW, Kim JH, Lee CS, Oh IY et al. Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation 2005; 112: 1618–1627.

    Article  PubMed  Google Scholar 

  46. Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 2004; 104: 2752–2760.

    Article  CAS  PubMed  Google Scholar 

  47. Prater DN, Case J, Ingram DA, Yoder MC . Working hypothesis to redefine endothelial progenitor cells. Leukemia 2007; 21: 1141–1149.

    Article  CAS  PubMed  Google Scholar 

  48. Bikfalvi A, Cramer EM, Tenza D, Tobelem G . Phenotypic modulations of human umbilical vein endothelial cells and human dermal fibroblasts using two angiogenic assays. Biol Cell 1991; 72: 275–278.

    Article  CAS  PubMed  Google Scholar 

  49. Taub M, Wang Y, Szczesny TM, Kleinman HK . Epidermal growth factor or transforming growth factor alpha is required for kidney tubulogenesis in matrigel cultures in serum-free medium. Proc Natl Acad Sci USA 1990; 87: 4002–4006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vernon RB, Angello JC, Iruela-Arispe ML, Lane TF, Sage EH . Reorganization of basement membrane matrices by cellular traction promotes the formation of cellular networks in vitro. Lab Invest 1992; 66: 536–547.

    CAS  PubMed  Google Scholar 

  51. Schmeisser A, Garlichs CD, Zhang H, Eskafi S, Graffy C, Ludwig J et al. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res 2001; 49: 671–680.

    Article  CAS  PubMed  Google Scholar 

  52. Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103: 2885–2890.

    Article  CAS  PubMed  Google Scholar 

  53. Schechner JS, Nath AK, Zheng L, Kluger MS, Hughes CC, Sierra-Honigmann MR et al. In vivo formation of complex microvessels lined by human endothelial cells in an immunodeficient mouse. Proc Natl Acad Sci USA 2000; 97: 9191–9196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Au P, Daheron LM, Duda DG, Cohen KS, Tyrrell JA, Lanning RM et al. Differential in vivo potential of endothelial progenitor cells from human umbilical cord blood and adult peripheral blood to form functional long-lasting vessels. Blood 2008; 111: 1302–1305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Au P, Tam J, Fukumura D, Jain RK . Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 2008; 111: 4551–4558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shepherd BR, Enis DR, Wang F, Suarez Y, Pober JS, Schechner JS . Vascularization and engraftment of a human skin substitute using circulating progenitor cell-derived endothelial cells. FASEB J 2006; 20: 1739–1741.

    Article  CAS  PubMed  Google Scholar 

  57. Nikolova T, Wu M, Brumbarov K, Alt R, Opitz H, Boheler KR et al. WNT-conditioned media differentially affect the proliferation and differentiation of cord blood-derived CD133+ cells in vitro. Differentiation 2007; 75: 100–111.

    Article  CAS  PubMed  Google Scholar 

  58. Kucia M, Wysoczynski M, Ratajczak J, Ratajczak MZ . Identification of very small embryonic like (VSEL) stem cells in bone marrow. Cell Tissue Res 2008; 331: 125–134.

    Article  CAS  PubMed  Google Scholar 

  59. Berger MJ, Adams SD, Tigges BM, Sprague SL, Wang XJ, Collins DP et al. Differentiation of umbilical cord blood-derived multilineage progenitor cells into respiratory epithelial cells. Cytotherapy 2006; 8: 480–487.

    Article  CAS  PubMed  Google Scholar 

  60. McNiece IK, Stoney GB, Kern BP, Briddell RA . CD34+ cell selection from frozen cord blood products using the Isolex 300i and CliniMACS CD34 selection devices. J Hematother 1998; 7: 457–461.

    Article  CAS  PubMed  Google Scholar 

  61. Aktas M, Radke TF, Strauer BE, Wernet P, Kogler G . Separation of adult bone marrow mononuclear cells using the automated closed separation system Sepax. Cytotherapy 2008; 10: 203–211.

    Article  CAS  PubMed  Google Scholar 

  62. Radke TF, Buchheiser A, Lefort A, Maleki M, Wernet P, Kogler G . GMP-conform generation and cultivation of USSC from cord blood using the SEPAX-separation method and a closed culture system applying cell stacks. Blood 2007; 110: 367 Abstract.

    Article  Google Scholar 

  63. Jager M, Degistirici O, Knipper A, Fischer J, Sager M, Krauspe R . Bone healing and migration of cord blood-derived stem cells into a critical size femoral defect after xenotransplantation. J Bone Miner Res 2007; 22: 1224–1233.

    Article  PubMed  Google Scholar 

  64. Degistirici O, Jager M, Knipper A . Applicability of cord blood-derived unrestricted somatic stem cells in tissue engineering concepts. Cell Prolif 2008; 41: 421–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nishiyama N, Miyoshi S, Hida N, Uyama T, Okamoto K, Ikegami Y et al. The significant cardiomyogenic potential of human umbilical cord blood-derived mesenchymal stem cells in vitro. Stem Cells 2007; 25: 2017–2024.

    Article  CAS  PubMed  Google Scholar 

  66. Kim BO, Tian H, Prasongsukarn K, Wu J, Angoulvant D, Wnendt S et al. Cell transplantation improves ventricular function after a myocardial infarction: a preclinical study of human unrestricted somatic stem cells in a porcine model. Circulation 2005; 112: I96–I104.

    PubMed  Google Scholar 

  67. Ghodsizad A, Niehaus M, Kogler G, Martin U, Wernet P, Bara C et al. Transplanted human cord blood-derived unrestricted somatic stem cells improve left-ventricular function and prevent left-ventricular dilation and scar formation after acute myocardial infarction. Heart 2009; 95: 27–35.

    Article  CAS  PubMed  Google Scholar 

  68. Chang SA, Lee EJ, Kang HJ, Zhan SY, Kim JH, Li L et al. Impact of myocardial infarct proteins and oscillating pressure on the differentiation of mesenchymal stem cells: effect of acute myocardial infarction on stem cell differentiation. Stem Cells 2008; 26: 1901–1912.

    Article  CAS  PubMed  Google Scholar 

  69. Leor J, Guetta E, Feinberg MS, Galski H, Bar I, Holbova R et al. Human umbilical cord blood-derived CD133+ cells enhance function and repair of the infarcted myocardium. Stem Cells 2006; 24: 772–780.

    Article  PubMed  Google Scholar 

  70. Bartsch T, Brehm M, Zeus T, Kogler G, Wernet P, Strauer BE . Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study). Clin Res Cardiol 2007; 96: 891–899.

    Article  CAS  PubMed  Google Scholar 

  71. Hoehn M, Kustermann E, Blunk J, Wiedermann D, Trapp T, Wecker S et al. Monitoring of implanted stem cell migration in vivo: a highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc Natl Acad Sci USA 2002; 99: 16267–16272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lindvall O, Kokaia Z . Stem cells for the treatment of neurological disorders. Nature 2006; 441: 1094–1096.

    Article  CAS  PubMed  Google Scholar 

  73. Vendrame M, Cassady J, Newcomb J, Butler T, Pennypacker KR, Zigova T et al. Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke 2004; 35: 2390–2395.

    Article  PubMed  Google Scholar 

  74. Kelly S, Bliss TM, Shah AK, Sun GH, Ma M, Foo WC et al. Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex. Proc Natl Acad Sci USA 2004; 101: 11839–11844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Erdo F, Buhrle C, Blunk J, Hoehn M, Xia Y, Fleischmann B et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab 2003; 23: 780–785.

    Article  PubMed  Google Scholar 

  76. Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE et al. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 2001; 32: 2682–2688.

    Article  CAS  PubMed  Google Scholar 

  77. Buzanska L, Machaj EK, Zablocka B, Pojda Z, Domanska-Janik K . Human cord blood-derived cells attain neuronal and glial features in vitro. J Cell Sci 2002; 115: 2131–2138.

    Article  CAS  PubMed  Google Scholar 

  78. Sun W, Buzanska L, Domanska-Janik K, Salvi RJ, Stachowiak MK . Voltage-sensitive and ligand-gated channels in differentiating neural stem-like cells derived from the nonhematopoietic fraction of human umbilical cord blood. Stem Cells 2005; 23: 931–945.

    Article  CAS  PubMed  Google Scholar 

  79. Newman MB, Willing AE, Manresa JJ, Sanberg CD, Sanberg PR . Cytokines produced by cultured human umbilical cord blood (HUCB) cells: implications for brain repair. Exp Neurol 2006; 199: 201–208.

    Article  CAS  PubMed  Google Scholar 

  80. Willing AE, Lixian J, Milliken M, Poulos S, Zigova T, Song S et al. Intravenous versus intrastriatal cord blood administration in a rodent model of stroke. J Neurosci Res 2003; 73: 296–307.

    Article  CAS  PubMed  Google Scholar 

  81. Xiao J, Nan Z, Motooka Y, Low WC . Transplantation of a novel cell line population of umbilical cord blood stem cells ameliorates neurological deficits associated with ischemic brain injury. Stem Cells Dev 2005; 14: 722–733.

    Article  CAS  PubMed  Google Scholar 

  82. Newcomb JD, Ajmo Jr CT, Sanberg CD, Pennypacker KR, Willing AE . Timing of cord blood treatment after experimental stroke determines therapeutic efficacy. Cell Transplant 2006; 15: 213–223.

    Article  PubMed  Google Scholar 

  83. Vendrame M, Gemma C, Pennypacker KR, Bickford PC, Bavis Sanberg C, Sanberg PR et al. Cord blood rescues stroke-induced changes in splenocyte phenotype and function. Exp Neurol 2006; 199: 191–200.

    Article  CAS  PubMed  Google Scholar 

  84. Nan Z, Grande A, Sanberg CD, Sanberg PR, Low WC . Infusion of human umbilical cord blood ameliorates neurologic deficits in rats with hemorrhagic brain injury. Ann NY Acad Sci 2005; 1049: 84–96.

    Article  PubMed  Google Scholar 

  85. Bliss T, Guzman R, Daadi M, Steinberg GK . Cell transplantation therapy for stroke. Stroke 2007; 38: 817–826.

    Article  PubMed  Google Scholar 

  86. Vendrame M, Gemma C, de Mesquita D, Collier L, Bickford PC, Sanberg CD et al. Anti-inflammatory effects of human cord blood cells in a rat model of stroke. Stem Cells Dev 2005; 14: 595–604.

    Article  CAS  PubMed  Google Scholar 

  87. Meier C, Middelanis J, Wasielewski B, Neuhoff S, Roth-Haerer A, Gantert M et al. Spastic paresis after perinatal brain damage in rats is reduced by human cord blood mononuclear cells. Pediatr Res 2006; 59: 244–249.

    Article  PubMed  Google Scholar 

  88. Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD, Sanberg PR . Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior. J Hematother Stem Cell Res 2003; 12: 271–278.

    Article  CAS  PubMed  Google Scholar 

  89. Kuh SU, Cho YE, Yoon DH, Kim KN, Ha Y . Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat. Acta Neurochir (Wien) 2005; 147: 985–992; discussion 992.

    Article  Google Scholar 

  90. Lu D, Sanberg PR, Mahmood A, Li Y, Wang L, Sanchez-Ramos J et al. Intravenous administration of human umbilical cord blood reduces neurological deficit in the rat after traumatic brain injury. Cell Transplant 2002; 11: 275–281.

    Article  PubMed  Google Scholar 

  91. Ende N, Chen R . Parkinson's disease mice and human umbilical cord blood. J Med 2002; 33: 173–180.

    PubMed  Google Scholar 

  92. Garbuzova-Davis S, Willing AE, Zigova T, Saporta S, Justen EB, Lane JC et al. Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematother Stem Cell Res 2003; 12: 255–270.

    Article  CAS  PubMed  Google Scholar 

  93. Ende N, Weinstein F, Chen R, Ende M . Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis). Life Sci 2000; 67: 53–59.

    Article  CAS  PubMed  Google Scholar 

  94. Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH et al. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 2004; 40: 1275–1284.

    Article  CAS  PubMed  Google Scholar 

  95. Ishikawa F, Drake CJ, Yang S, Flemming P, Minamiguchi H, Visconti RP et al. Transplanted human cord blood cells give rise to hepatocytes in engrafted mice. Ann NY Acad Sci 2003; 996: 174–185.

    Article  CAS  PubMed  Google Scholar 

  96. Minamiguchi H, Ishikawa F, Fleming PA, Yang S, Drake CJ, Wingard JR et al. Transplanted human cord blood cells generate amylase-producing pancreatic acinar cells in engrafted mice. Pancreas 2008; 36: e30–e35.

    Article  CAS  PubMed  Google Scholar 

  97. Furst G, Schulte am Esch J, Poll LW, Hosch SB, Fritz LB, Klein M et al. Portal vein embolization and autologous CD133+ bone marrow stem cells for liver regeneration: initial experience. Radiology 2007; 243: 171–179.

    Article  PubMed  Google Scholar 

  98. Haller MJ, Viener HL, Wasserfall C, Brusko T, Atkinson MA, Schatz DA . Autologous umbilical cord blood infusion for type 1 diabetes. Exp Hematol 2008; 36: 710–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chan SL, Choi M, Wnendt S, Kraus M, Teng E, Leong HF et al. Enhanced in vivo homing of uncultured and selectively amplified cord blood CD34+ cells by cotransplantation with cord blood-derived unrestricted somatic stem cells. Stem Cells 2007; 25: 529–536.

    Article  CAS  PubMed  Google Scholar 

  100. Riordan NH, Chan K, Marleau AM, Ichim TE . Cord blood in regenerative medicine: do we need immune suppression? J Transl Med 2007; 5: 8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Kim SW, Han H, Chae GT, Lee SH, Bo S, Yoon JH et al. Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger's disease and ischemic limb disease animal model. Stem Cells 2006; 24: 1620–1626.

    Article  PubMed  Google Scholar 

  102. Kang KS, Kim SW, Oh YH, Yu JW, Kim KY, Park HK et al. A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human UC blood, with improved sensory perception and mobility, both functionally and morphologically: a case study. Cytotherapy 2005; 7: 368–373.

    Article  PubMed  Google Scholar 

  103. Valbonesi M, Giannini G, Migliori F, Dalla Costa R, Dejana AM . Cord blood (CB) stem cells for wound repair. Preliminary report of 2 cases. Transfus Apher Sci 2004; 30: 153–156.

    Article  CAS  PubMed  Google Scholar 

  104. Winter M, Wang XN, Däubener W, Eyking A, Rae M, Dickinson AM et al. Suppression of cellular immunity by cord blood-derived unrestricted somatic stem cells is cytokine dependent. J Cell Mol Med 2008 (e-pub ahead of print 19175687).

  105. Berk Vd, Jansen BJH, Siebers-Vermeulen KGC, Netea M, Latuhihin T, Bergovoet S et al. Toll-like receptor triggering shows restricted cytokine secretion and alters differentiation kinetics of cord blood derived mesenchymal stem cells. J Cell Mol Med 2008 (e-pub ahead of print 19153239).

  106. Regenberg A, Mathews DJ, Blass DM, Bok H, Coyle JT, Duggan P et al. The role of animal models in evaluating reasonable safety and efficacy for human trials of cell-based interventions for neurologic conditions. J Cereb Blood Flow Metab 2009; 29: 1–9.

    Article  PubMed  Google Scholar 

  107. Weber R, Ramos-Cabrer P, Justicia C, Wiedermann D, Strecker C, Sprenger C et al. Early prediction of functional recovery after experimental stroke: functional magnetic resonance imaging, electrophysiology, and behavioral testing in rats. J Neurosci 2008; 28: 1022–1029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Jager M, Sager M, Knipper A, Degistririci O, Fischer J, Kogler G et al. In vivo and in vitro bone regeneration from cord blood derived mesenchymal stem cells]. Orthopade 2004; 33: 1361–1372.

    Article  CAS  PubMed  Google Scholar 

  109. Fallahi-Sichani M, Soleimani M, Najafi SM, Kiani J, Arefian E, Atashi A . In vitro differentiation of cord blood unrestricted somatic stem cells expressing dopamine-associated genes into neuron-like cells. Cell Biol Int 2007; 31: 299–303.

    Article  CAS  PubMed  Google Scholar 

  110. Lu FZ, Fujino M, Kitazawa Y, Uyama T, Hara Y, Funeshima N et al. Characterization and gene transfer in mesenchymal stem cells derived from human umbilical-cord blood. J Lab Clin Med 2005; 146: 271–278.

    Article  CAS  PubMed  Google Scholar 

  111. Chang YJ, Shih DT, Tseng CP, Hsieh TB, Lee DC, Hwang SM . Disparate mesenchyme-lineage tendencies in mesenchymal stem cells from human bone marrow and umbilical cord blood. Stem Cells 2006; 24: 679–685.

    Article  CAS  PubMed  Google Scholar 

  112. Lu LL, Liu YJ, Yang SG, Zhao QJ, Wang X, Gong W et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 2006; 91: 1017–1026.

    CAS  PubMed  Google Scholar 

  113. Kim JS, Lee HK, Kim MR, Kim PK, Kim CW . Differentially expressed proteins of mesenchymal stem cells derived from human cord blood (hUCB) during osteogenic differentiation. Biosci Biotechnol Biochem 2008; 72: 2309–2317.

    Article  CAS  PubMed  Google Scholar 

  114. Jeong JA, Gang EJ, Hong SH, Hwang SH, Kim SW, Yang IH et al. Rapid neural differentiation of human cord blood-derived mesenchymal stem cells. Neuroreport 2004; 15: 1731–1734.

    Article  CAS  PubMed  Google Scholar 

  115. Wang TT, Tio M, Lee W, Beerheide W, Udolph G . Neural differentiation of mesenchymal-like stem cells from cord blood is mediated by PKA. Biochem Biophys Res Commun 2007; 357: 1021–1027.

    Article  CAS  PubMed  Google Scholar 

  116. Kim SJ, Lee JK, Kim JW, Jung JW, Seo K, Park SB et al. Surface modification of polydimethylsiloxane (PDMS) induced proliferation and neural-like cells differentiation of umbilical cord blood-derived mesenchymal stem cells. J Mater Sci Mater Med 2008; 19: 2953–2962.

    Article  CAS  PubMed  Google Scholar 

  117. Song S, Sanchez-Ramos J . Preparation of neural progenitors from bone marrow and umbilical cord blood. Methods Mol Biol 2008; 438: 123–134.

    Article  CAS  PubMed  Google Scholar 

  118. Fu YS, Cheng YC, Lin MY, Cheng H, Chu PM, Chou SC et al. Conversion of human umbilical cord mesenchymal stem cells in Wharton's jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells 2006; 24: 115–124.

    Article  PubMed  Google Scholar 

  119. Garbuzova-Davis S, Willing AE, Saporta S, Bickford PC, Gemma C, Chen N et al. Novel cell therapy approaches for brain repair. Prog Brain Res 2006; 157: 207–222.

    Article  CAS  PubMed  Google Scholar 

  120. Ding DC, Shyu WC, Chiang MF, Lin SZ, Chang YC, Wang HJ et al. Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis 2007; 27: 339–353.

    Article  CAS  PubMed  Google Scholar 

  121. Kozlowska H, Jablonka J, Janowski M, Jurga M, Kossut M, Domanska-Janik K . Transplantation of a novel human cord blood-derived neural-like stem cell line in a rat model of cortical infarct. Stem Cells Dev 2007; 16: 481–488.

    Article  PubMed  Google Scholar 

  122. Domanska-Janik K, Buzanska L, Lukomska B . A novel, neural potential of non-hematopoietic human umbilical cord blood stem cells. Int J Dev Biol 2008; 52: 237–248.

    Article  PubMed  Google Scholar 

  123. Hill AJ, Zwart I, Tam HH, Chan J, Navarrete C, Jen LS et al. Human umbilical cord blood-derived mesenchymal stem cells do not differentiate into neural cells types or integrate into the retina after intravitreal grafting in neonatal rats. Stem Cells Dev 2009; 18: 399–409.

    Article  CAS  PubMed  Google Scholar 

  124. Hong SH, Gang EJ, Jeong JA, Ahn C, Hwang SH, Yang IH et al. In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells. Biochem Biophys Res Commun 2005; 330: 1153–1161.

    Article  CAS  PubMed  Google Scholar 

  125. Kang XQ, Zang WJ, Bao LJ, Li DL, Song TS, Xu XL et al. Fibroblast growth factor-4 and hepatocyte growth factor induce differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocytes. World J Gastroenterol 2005; 11: 7461–7465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kubota H, Storms RW, Reid LM . Variant forms of alpha-fetoprotein transcripts expressed in human hematopoietic progenitors. Implications for their developmental potential towards endoderm. J Biol Chem 2002; 277: 27629–27635.

    Article  CAS  PubMed  Google Scholar 

  127. Habich A, Jurga M, Markiewicz I, Lukomska B, Bany-Laszewicz U, Domanska-Janik K . Early appearance of stem/progenitor cells with neural-like characteristics in human cord blood mononuclear fraction cultured in vitro. Exp Hematol 2006; 34: 914–925.

    Article  CAS  PubMed  Google Scholar 

  128. Buzanska L, Jurga M, Domanska-Janik K . Neuronal differentiation of human umbilical cord blood neural stem-like cell line. Neurodegener Dis 2006; 3: 19–26.

    Article  PubMed  Google Scholar 

  129. Buzanska L, Jurga M, Stachowiak EK, Stachowiak MK, Domanska-Janik K . Neural stem-like cell line derived from a nonhematopoietic population of human umbilical cord blood. Stem Cells Dev 2006; 15: 391–406.

    Article  CAS  PubMed  Google Scholar 

  130. Lee MW, Moon YJ, Yang MS, Kim SK, Jang IK, Eom YW et al. Neural differentiation of novel multipotent progenitor cells from cryopreserved human umbilical cord blood. Biochem Biophys Res Commun 2007; 358: 637–643.

    Article  CAS  PubMed  Google Scholar 

  131. Tracy E, Aldrink J, Panosian J, Beam D, Thacker J, Reese M et al. Isolation of oligodendrocyte-like cells from human umbilical cord blood. Cytotherapy 2008; 10: 518–525.

    Article  CAS  PubMed  Google Scholar 

  132. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M et al. Axonal remyelination by cord blood stem cells after spinal cord injury. J Neurotrauma 2007; 24: 391–410.

    Article  PubMed  Google Scholar 

  133. Walczak P, Chen N, Eve D, Hudson J, Zigova T, Sanchez-Ramos J et al. Long-term cultured human umbilical cord neural-like cells transplanted into the striatum of NOD SCID mice. Brain Res Bull 2007; 74: 155–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cho SR, Yang MS, Yim SH, Park JH, Lee JE, Eom YW et al. Neurally induced umbilical cord blood cells modestly repair injured spinal cords. Neuroreport 2008; 19: 1259–1263.

    Article  PubMed  Google Scholar 

  135. Moon YJ, Lee MW, Yoon HH, Yang MS, Jang IK, Lee JE et al. Hepatic differentiation of cord blood-derived multipotent progenitor cells (MPCs) in vitro. Cell Biol Int 2008; 32: 1293–1301.

    Article  CAS  PubMed  Google Scholar 

  136. Drewel D, Luecke K, Mueller G, Kunz-Schughart LA, Dietl B, Zeitler I et al. SCF modulates organ distribution and hematopoietic engraftment of CB-derived pluripotent HPC transplanted in NOD/SCID mice. Cytotherapy 2006; 8: 70–78.

    Article  CAS  PubMed  Google Scholar 

  137. Tang XP, Zhang M, Yang X, Chen LM, Zeng Y . Differentiation of human umbilical cord blood stem cells into hepatocytes in vivo and in vitro. World J Gastroenterol 2006; 12: 4014–4019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sun Y, Xiao D, Zhang RS, Cui GH, Wang XH, Chen CG . Formation of human hepatocyte-like cells with different cellular phenotypes by human umbilical cord blood-derived cells in the human-rat chimeras. Biochem Biophys Res Commun 2007; 357: 1160–1165.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank all the co-authors of our jointly published papers that were cited here and the Deutsche Forschungsgemeinschaft (DFG) for funding the research group FOR 717 including the project Ko2119/6-1. Studies reported from the author's laboratory concerning the hematopoiesis-supporting activity, which were reviewed here, have been supported by the German José Carreras Leukemia Foundation grant DJCLS-R03/06; DJCLS-R07/05v. Thanks to Teja Radke, S Maria Kluth, Aurelie Lefort and Anja Buchheiser, PhD, for their excellent technical support and Karen Mattheisen for reading the paper. G Kögler personally thank E Gluckman, who introduced me into the world of cord blood and motivated me all along the way.

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Kögler, G., Critser, P., Trapp, T. et al. Future of cord blood for non-oncology uses. Bone Marrow Transplant 44, 683–697 (2009). https://doi.org/10.1038/bmt.2009.287

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