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Cord Blood Stem Cell Expansion Ex Vivo: Current Status and Future Strategies

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Abstract

Reconstitution of immune system with allogeneic hematopoietic stem cells (HSCs) appears to be critical for the cure of hematopoietic malignancies and advanced autoimmune diseases. Cord blood (CB) HSCs is an ideal resource for the reconstitution. However, the number of HSCs in each CB unit is not sufficient for the patients who require multiple HSC transplantations. Large ex vivo expansion of transplantable CB HSCs may overcome the difficulty. Ideally, the expanded CB HSCs should be safe without the risk of cell transformation, preserve the capability of self-renewal and multipotency of differentiation, and be competent in long-term repopulation. Although we are far away from the criteria, recently, ex vivo expansion of CB HSCs has been extensively investigated in line with the progress in stem cell biology, and would bring a huge hope for cure of diseases by transplantation of CB HSCs. In this chapter, we will review the recent progress in ex vivo expansion of CB HSCs as well as current understandings of HSCs, including cellular and molecular bases useful for ex vivo expansion of HSCs.

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References

  1. Gluckman EG, Roch VV, Chastang C. Use of cord blood cells for banking and transplant. Oncologist. 1997;2:340-343.

    PubMed  Google Scholar 

  2. Tse W, Bunting KD, Laughlin MJ. New insights into cord blood stem cell transplantation. Curr Opin Hematol. 2008;15:279-284.

    PubMed  Google Scholar 

  3. Brown JA, Boussiotis VA. Umbilical cord blood transplantation: basic biology and clinical challenges to immune reconstitution. Clin Immunol. 2008;127:286-297.

    CAS  PubMed  Google Scholar 

  4. Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 1997;337:373-381.

    CAS  PubMed  Google Scholar 

  5. Kondo M, Wagers AJ, Manz MG, et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol. 2003;21:759-806.

    CAS  PubMed  Google Scholar 

  6. Morrison SJ, Uchida N, Weissman IL. The biology of hema­topoietic stem cells. Annu Rev Cell Dev Biol. 1995;11:35-71.

    CAS  PubMed  Google Scholar 

  7. Li L, Xie T. Stem cell niche: structure and function. Annu Rev Cell Dev Biol. 2005;21:605-631.

    CAS  PubMed  Google Scholar 

  8. Moore KA, Lemischka IR. Stem cells and their niches. Science. 2006;311:1880-1885.

    CAS  PubMed  Google Scholar 

  9. Gao JX. Cancer stem cells: the lessons from precancerous stem cells. J Cell Mol Med. 2008;12:67-96.

    CAS  PubMed  Google Scholar 

  10. Brazelton TR, Rossi FM, Keshet GI, et al. From marrow to brain: expression of neuronal phenotypes in adult mice. Science. 2000;290:1775-1779.

    CAS  PubMed  Google Scholar 

  11. Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA. 1999;96:10711-10716.

    CAS  PubMed  Google Scholar 

  12. Zhao LR, Duan WM, Reyes M, et al. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol. 2002;174:11-20.

    PubMed  Google Scholar 

  13. Theise ND, Badve S, Saxena R, et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology. 2000;31:235-240.

    CAS  PubMed  Google Scholar 

  14. Tang XP, Zhang M, Yang X, et al. Differentiation of human umbilical cord blood stem cells into hepatocytes in vivo and in vitro. World J Gastroenterol. 2006;12:4014-4019.

    CAS  PubMed  Google Scholar 

  15. Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA. 1999;96:14482-14486.

    CAS  PubMed  Google Scholar 

  16. Camargo FD, Green R, Capetanaki Y, et al. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med. 2003;9:1520-1527.

    CAS  PubMed  Google Scholar 

  17. Abedi M, Foster BM, Wood KD, et al. Haematopoietic stem cells participate in muscle regeneration. Br J Haematol. 2007;138:792-801.

    PubMed  Google Scholar 

  18. Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001;107:1395-1402.

    CAS  PubMed  Google Scholar 

  19. Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA. 2001;98:10344-10349.

    CAS  PubMed  Google Scholar 

  20. Kajstura J, Rota M, Whang B, et al. Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion. Circ Res. 2005;96:127-137.

    CAS  PubMed  Google Scholar 

  21. Nygren JM, Jovinge S, Breitbach M, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med. 2004;10:494-501.

    CAS  PubMed  Google Scholar 

  22. Balsam LB, Wagers AJ, Christensen JL, et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004;428:668-673.

    CAS  PubMed  Google Scholar 

  23. Rizvi AZ, Swain JR, Davies PS, et al. Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Natl Acad Sci USA. 2006;103:6321-6325.

    CAS  PubMed  Google Scholar 

  24. Murry CE, Soonpaa MH, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004;428:664-668.

    CAS  PubMed  Google Scholar 

  25. Orlic D. BM stem cells and cardiac repair: where do we stand in 2004? Cytotherapy. 2005;7:3-15.

    CAS  PubMed  Google Scholar 

  26. Brown JM, Weissman IL. Progress and prospects in hematopoietic stem cell expansion and transplantation. Exp Hematol. 2004;32:693-695.

    CAS  PubMed  Google Scholar 

  27. Mazurier F, Doedens M, Gan OI, et al. Characterization of cord blood hematopoietic stem cells. Ann NY Acad Sci. 2003;996:67-71.

    PubMed  Google Scholar 

  28. Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003;348:255-256.

    PubMed  Google Scholar 

  29. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415-419.

    CAS  PubMed  Google Scholar 

  30. Amsellem S, Pflumio F, Bardinet D, et al. Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Nat Med. 2003;9:1423-1427.

    CAS  PubMed  Google Scholar 

  31. Krosl J, Austin P, Beslu N, et al. In vitro expansion of hematopoietic stem cells by recombinant TAT-HOXB4 protein. Nat Med. 2003;9:1428-1432.

    CAS  PubMed  Google Scholar 

  32. Breems DA, Blokland EA, Siebel KE, et al. Stroma-contact prevents loss of hematopoietic stem cell quality during ex vivo expansion of CD34+ mobilized peripheral blood stem cells. Blood. 1998;91:111-117.

    CAS  PubMed  Google Scholar 

  33. Bennaceur-Griscelli A, Tourino C, Izac B, et al. Murine stromal cells counteract the loss of long-term culture-initiating cell potential induced by cytokines in CD34(+)CD38(low/neg) human bone marrow cells. Blood. 1999;94:529-538.

    CAS  PubMed  Google Scholar 

  34. Kawano Y, Kobune M, Yamaguchi M, et al. Ex vivo expansion of human umbilical cord hematopoietic progenitor cells using a coculture system with human telomerase catalytic subunit (hTERT)-transfected human stromal cells. Blood. 2003;101:532-540.

    CAS  PubMed  Google Scholar 

  35. Yang YX, Miao ZC, Zhang HJ, et al. Establishment and characterization of a human telomerase catalytic subunit-transduced fetal bone marrow-derived osteoblastic cell line. Differentiation. 2007;75:24-34.

    CAS  PubMed  Google Scholar 

  36. Li Y, Ma T, Kniss DA, et al. Human cord cell hematopoiesis in three-dimensional nonwoven fibrous matrices: in vitro simulation of the marrow microenvironment. J Hematother Stem Cell Res. 2001;10:355-368.

    CAS  PubMed  Google Scholar 

  37. Okamoto T, Takagi M, Soma T, et al. Effect of heparin addition on expansion of cord blood hematopoietic progenitor cells in three-dimensional coculture with stromal cells in nonwoven fabrics. J Artif Organs. 2004;7:194-202.

    CAS  PubMed  Google Scholar 

  38. Takagi M. Cell processing engineering for ex-vivo expansion of hematopoietic cells. J Biosci Bioeng. 2005;99:189-196.

    CAS  PubMed  Google Scholar 

  39. Sands RW, Mooney DJ. Polymers to direct cell fate by controlling the microenvironment. Curr Opin Biotechnol. 2007;18:448-453.

    CAS  PubMed  Google Scholar 

  40. Zhang CC, Lodish HF. Cytokines regulating hematopoietic stem cell function. Curr Opin Hematol. 2008;15:307-311.

    CAS  PubMed  Google Scholar 

  41. Yamaguchi M, Hirayama F, Kanai M, et al. Serum-free coculture system for ex vivo expansion of human cord blood primitive progenitors and SCID mouse-reconstituting cells using human bone marrow primary stromal cells. Exp Hematol. 2001;29:174-182.

    CAS  PubMed  Google Scholar 

  42. Chen L, Shen R, Ye Y, et al. Precancerous stem cells have the potential for both benign and malignant differentiation. PLoS ONE. 2007;2:e293.

    PubMed  Google Scholar 

  43. Skea D, Chang NH, Hedge R, et al. Large ex vivo expansion of human umbilical cord blood CD4+ and CD8+ T cells. J Hematother. 1999;8:129-139.

    CAS  PubMed  Google Scholar 

  44. Skea D, Hedge R, Dabek B, et al. The selective expansion of functional T cell subsets. J Hematother Stem Cell Res. 1999;8:525-538.

    CAS  PubMed  Google Scholar 

  45. Larochelle A, Vormoor J, Hanenberg H, et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nat Med. 1996;2:1329-1337.

    CAS  PubMed  Google Scholar 

  46. Dick JE, Bhatia M, Gan O, et al. Assay of human stem cells by repopulation of NOD/SCID mice. Stem Cells. 1997;15(Suppl 1):199-203. discussion 204–197.

    PubMed  Google Scholar 

  47. Keating A. Mesenchymal stromal cells. Curr Opin Hematol. 2006;13:419-425.

    PubMed  Google Scholar 

  48. Jones DL, Wagers AJ. No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol. 2008;9:11-21.

    CAS  PubMed  Google Scholar 

  49. Yin T, Li L. The stem cell niches in bone. J Clin Invest. 2006;116:1195-1201.

    CAS  PubMed  Google Scholar 

  50. Arai F, Suda T. Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche. Ann NY Acad Sci. 2007;1106:41-53.

    CAS  PubMed  Google Scholar 

  51. Martinez-Agosto JA, Mikkola HK, Hartenstein V, et al. The hematopoietic stem cell and its niche: a comparative view. Genes Dev. 2007;21:3044-3060.

    CAS  PubMed  Google Scholar 

  52. Metcalf D. On hematopoietic stem cell fate. Immunity. 2007;26:669-673.

    CAS  PubMed  Google Scholar 

  53. Deng W, Lin H. Asymmetric germ cell division and oocyte determination during Drosophila oogenesis. Int Rev Cytol. 2001;203:93-138.

    CAS  PubMed  Google Scholar 

  54. Knoblich JA. Mechanisms of asymmetric stem cell division. Cell. 2008;132:583-597.

    CAS  PubMed  Google Scholar 

  55. Seoh JY, Woo SY, Im SA, et al. Distinct patterns of apoptosis in association with modulation of CD44 induced by thrombopoietin and granulocyte-colony stimulating factor during ex vivo expansion of human cord blood CD34+ cells. Br J Haematol. 1999;107:176-185.

    CAS  PubMed  Google Scholar 

  56. Domen J, Weissman IL. Hematopoietic stem cells need two signals to prevent apoptosis; BCL-2 can provide one of these, Kitl/c-Kit signaling the other. J Exp Med. 2000;192:1707-1718.

    CAS  PubMed  Google Scholar 

  57. Domen J, Cheshier SH, Weissman IL. The role of apoptosis in the regulation of hematopoietic stem cells: overexpression of Bcl-2 increases both their number and repopulation potential. J Exp Med. 2000;191:253-264.

    CAS  PubMed  Google Scholar 

  58. Oguro H, Iwama A. Life and death in hematopoietic stem cells. Curr Opin Immunol. 2007;19:503-509.

    CAS  PubMed  Google Scholar 

  59. Bieback K, Kern S, Kocaomer A, et al. 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 

  60. Chen CP, Lee MY, Huang JP, et al. Trafficking of multipotent mesenchymal stromal cells from maternal circulation through the placenta involves vascular endothelial growth factor receptor-1 and integrins. Stem Cells. 2008;26:550-561.

    CAS  PubMed  Google Scholar 

  61. Zhang Y, Chai C, Jiang XS, et al. Co-culture of umbilical cord blood CD34+ cells with human mesenchymal stem cells. Tissue Eng. 2006;12:2161-2170.

    PubMed  Google Scholar 

  62. Friedman R, Betancur M, Boissel L, et al. Umbilical cord mesenchymal stem cells: adjuvants for human cell transplantation. Biol Blood Marrow Transplant. 2007;13:1477-1486.

    PubMed  Google Scholar 

  63. Hu L, Cheng L, Wang J, et al. Effects of human yolk sac endothelial cells on supporting expansion of hematopoietic stem/progenitor cells from cord blood. Cell Biol Int. 2006;30:879-884.

    CAS  PubMed  Google Scholar 

  64. Ma LJ, Gao L, Zhou H, et al. Effects of human mesenchymal stem cells and fibroblastoid cell line as feeder layers on expansion of umbilical cord blood CD34(+) cells in vitro. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2006;14:949-954.

    CAS  PubMed  Google Scholar 

  65. Chen HQ, Zhang XC, Tang XY, et al. Hematopoietic growth factors expressed in human aorta-gonad-mesonephros (AGM)-derived stromal cells in vitro. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2006;14:999-1003.

    CAS  PubMed  Google Scholar 

  66. Ito Y, Hasauda H, Kitajima T, et al. Ex vivo expansion of human cord blood hematopoietic progenitor cells using glutaraldehyde-fixed human bone marrow stromal cells. J Biosci Bioeng. 2006;102:467-469.

    CAS  PubMed  Google Scholar 

  67. Chua KN, Chai C, Lee PC, et al. Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells. Exp Hematol. 2007;35:771-781.

    CAS  PubMed  Google Scholar 

  68. Uchida N, Aguila HL, Fleming WH, et al. Rapid and sustained hematopoietic recovery in lethally irradiated mice transplanted with purified Thy-1.1lo Lin-Sca-1+ hematopoietic stem cells. Blood. 1994;83:3758-3779.

    CAS  PubMed  Google Scholar 

  69. Uchida N, Jerabek L, Weissman IL. Searching for hematopoietic stem cells. II. The heterogeneity of Thy-1.1(lo)Lin(-/lo)Sca-1+ mouse hematopoietic stem cells separated by counterflow centrifugal elutriation. Exp Hematol. 1996;24:649-659.

    CAS  PubMed  Google Scholar 

  70. Uchida N, Weissman IL. Searching for hematopoietic stem cells: evidence that Thy-1.1lo Lin- Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow. J Exp Med. 1992;175:175-184.

    CAS  PubMed  Google Scholar 

  71. Engelhardt M, Lubbert M, Guo Y. CD34(+) or CD34(-): which is the more primitive? Leukemia. 2002;16:1603-1608.

    CAS  PubMed  Google Scholar 

  72. Majeti R, Park CY, Weissman IL. Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell. 2007;1:635-645.

    CAS  PubMed  Google Scholar 

  73. Hess DA, Karanu FN, Levac K, et al. Coculture and transplant of purified CD34(+)Lin(-) and CD34(-)Lin(-) cells reveals functional interaction between repopulating hematopoietic stem cells. Leukemia. 2003;17:1613-1625.

    CAS  PubMed  Google Scholar 

  74. Petzer AL, Hogge DE, Landsdorp PM, et al. Self-renewal of primitive human hematopoietic cells (long-term-culture-initiating cells) in vitro and their expansion in defined medium. Proc Natl Acad Sci USA. 1996;93:1470-1474.

    CAS  PubMed  Google Scholar 

  75. Yang S, Cai H, Jin H, et al. Hematopoietic reconstitution of CD34+ cells grown in static and stirred culture systems in NOD/SCID mice. Biotechnol Lett. 2008;30:61-65.

    CAS  PubMed  Google Scholar 

  76. Fujimoto N, Fujita S, Tsuji T, et al. Microencapsulated feeder cells as a source of soluble factors for expansion of CD34+ hematopoietic stem cells. Biomaterials. 2007;28:4795-4805.

    CAS  PubMed  Google Scholar 

  77. Brunstein CG, Setubal DC, Wagner JE. Expanding the role of umbilical cord blood transplantation. Br J Haematol. 2007;137:20-35.

    PubMed  Google Scholar 

  78. Tanaka J, Sugita J, Kato N, et al. Expansion of natural killer cell receptor (CD94/NKG2A)-expressing cytolytic CD8 T cells and CD4 + CD25+ regulatory T cells from the same cord blood unit. Exp Hematol. 2007;35:1562-1566.

    CAS  PubMed  Google Scholar 

  79. Constantinescu S. Stemness, fusion and renewal of hematopoietic and embryonic stem cells. J Cell Mol Med. 2003;7:103-112.

    CAS  PubMed  Google Scholar 

  80. Campbell C, Risueno RM, Salati S, et al. Signal control of hematopoietic stem cell fate: Wnt, Notch, and Hedgehog as the usual suspects. Curr Opin Hematol. 2008;15:319-325.

    CAS  PubMed  Google Scholar 

  81. Chickarmane V, Troein C, Nuber UA, et al. Transcriptional dynamics of the embryonic stem cell switch. PLoS Comput Biol. 2006;2:e123.

    PubMed  Google Scholar 

  82. Imamura M, Miura K, Iwabuchi K, et al. Transcriptional repression and DNA hypermethylation of a small set of ES cell marker genes in male germline stem cells. BMC Dev Biol. 2006;6:34.

    PubMed  Google Scholar 

  83. Guo Y, Mantel C, Hromas RA, et al. Oct-4 is critical for survival/antiapoptosis of murine embryonic stem cells subjected to stress: effects associated with Stat3/Survivin. Stem Cells. 2008;26:30-34.

    CAS  PubMed  Google Scholar 

  84. Chambers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003;113:643-655.

    CAS  PubMed  Google Scholar 

  85. Chambers I, Silva J, Colby D, et al. Nanog safeguards pluripotency and mediates germline development. Nature. 2007;450:1230-1234.

    CAS  PubMed  Google Scholar 

  86. Nichols J, Zevnik B, Anastassiadis K, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998;95:379-391.

    CAS  PubMed  Google Scholar 

  87. Silva J, Smith A. Capturing pluripotency. Cell. 2008;132:532-536.

    CAS  PubMed  Google Scholar 

  88. Jaenisch R, Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008;132:567-582.

    CAS  PubMed  Google Scholar 

  89. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861-872.

    CAS  PubMed  Google Scholar 

  90. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663-676.

    CAS  PubMed  Google Scholar 

  91. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917-1920.

    CAS  PubMed  Google Scholar 

  92. Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132:631-644.

    CAS  PubMed  Google Scholar 

  93. Teitell MA, Mikkola HK. Transcriptional activators, repressors, and epigenetic modifiers controlling hematopoietic stem cell development. Pediatr Res. 2006;59:33R-39R.

    CAS  PubMed  Google Scholar 

  94. Rosenbauer F, Tenen DG. Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol. 2007;7:105-117.

    CAS  PubMed  Google Scholar 

  95. Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66:6063-6071.

    CAS  PubMed  Google Scholar 

  96. Raaphorst FM. Self-renewal of hematopoietic and leukemic stem cells: a central role for the Polycomb-group gene Bmi-1. Trends Immunol. 2003;24:522-524.

    CAS  PubMed  Google Scholar 

  97. Orkin SH. Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet. 2000;1:57-64.

    CAS  PubMed  Google Scholar 

  98. Blank U, Karlsson G, Karlsson S. Signaling pathways governing stem-cell fate. Blood. 2008;111:492-503.

    CAS  PubMed  Google Scholar 

  99. Bhardwaj G, Murdoch B, Wu D, et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol. 2001;2:172-180.

    CAS  PubMed  Google Scholar 

  100. Bhatia M, Bonnet D, Wu D, et al. Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells. J Exp Med. 1999;189:1139-1148.

    CAS  PubMed  Google Scholar 

  101. Eaves CJ. Manipulating hematopoietic stem cell amplification with Wnt. Nat Immunol. 2003;4:511-512.

    CAS  PubMed  Google Scholar 

  102. Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423:409-414.

    CAS  PubMed  Google Scholar 

  103. Willert K, Brown JD, Danenberg E, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423:448-452.

    CAS  PubMed  Google Scholar 

  104. Karanu FN, Murdoch B, Gallacher L, et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med. 2000;192:1365-1372.

    CAS  PubMed  Google Scholar 

  105. Karanu FN, Yuefei L, Gallacher L, et al. Differential response of primitive human CD34- and CD34+ hematopoietic cells to the Notch ligand Jagged-1. Leukemia. 2003;17:1366-1374.

    CAS  PubMed  Google Scholar 

  106. Murdoch B, Chadwick K, Martin M, et al. Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc Natl Acad Sci USA. 2003;100:3422-3427.

    CAS  PubMed  Google Scholar 

  107. Reya T. Regulation of hematopoietic stem cell self-renewal. Recent Prog Horm Res. 2003;58:283-295.

    CAS  PubMed  Google Scholar 

  108. Look AT. Oncogenic transcription factors in the human acute leukemias. Science. 1997;278:1059-1064.

    CAS  PubMed  Google Scholar 

  109. Buske C, Humphries RK. Homeobox genes in leukemogenesis. Int J Hematol. 2000;71:301-308.

    CAS  PubMed  Google Scholar 

  110. Kirito K, Fox N, Kaushansky K. Thrombopoietin stimulates Hoxb4 expression: an explanation for the favorable effects of TPO on hematopoietic stem cells. Blood. 2003;102:3172-3178.

    PubMed  Google Scholar 

  111. Krosl J, Beslu N, Mayotte N, et al. The competitive nature of HOXB4-transduced HSC is limited by PBX1: the generation of ultra-competitive stem cells retaining full differentiation potential. Immunity. 2003;18:561-571.

    CAS  PubMed  Google Scholar 

  112. Antonchuk J, Sauvageau G, Humphries RK. HOXB4 overexpression mediates very rapid stem cell regeneration and competitive hematopoietic repopulation. Exp Hematol. 2001;29:1125-1134.

    CAS  PubMed  Google Scholar 

  113. Kopan R. Notch: a membrane-bound transcription factor. J Cell Sci. 2002;115:1095-1097.

    CAS  PubMed  Google Scholar 

  114. Hurlbut GD, Kankel MW, Lake RJ, et al. Crossing paths with Notch in the hyper-network. Curr Opin Cell Biol. 2007;19:166-175.

    CAS  PubMed  Google Scholar 

  115. Varnum-Finney B, Xu L, Brashem-Stein C, et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med. 2000;6:1278-1281.

    CAS  PubMed  Google Scholar 

  116. Larsson J, Karlsson S. The role of Smad signaling in hematopoiesis. Oncogene. 2005;24:5676-5692.

    CAS  PubMed  Google Scholar 

  117. Kunath T, Saba-El-Leil MK, Almousailleakh M, et al. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development. 2007;134:2895-2902.

    CAS  PubMed  Google Scholar 

  118. Sekkai D, Gruel G, Herry M, et al. Microarray analysis of LIF/Stat3 transcriptional targets in embryonic stem cells. Stem Cells. 2005;23:1634-1642.

    CAS  PubMed  Google Scholar 

  119. Sato N, Meijer L, Skaltsounis L, et al. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004;10:55-63.

    CAS  PubMed  Google Scholar 

  120. Trowbridge JJ, Xenocostas A, Moon RT, et al. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med. 2006;12:89-98.

    CAS  PubMed  Google Scholar 

  121. Audet J, Miller CL, Eaves CJ, et al. Common and distinct features of cytokine effects on hematopoietic stem and progenitor cells revealed by dose-response surface analysis. Biotechnol Bioeng. 2002;80:393-404.

    CAS  PubMed  Google Scholar 

  122. Conneally E, Cashman J, Petzer A, et al. Expansion in vitro of transplantable human cord blood stem cells demonstrated using a quantitative assay of their lympho-myeloid repopulating activity in nonobese diabetic-scid/scid mice. Proc Natl Acad Sci USA. 1997;94:9836-9841.

    CAS  PubMed  Google Scholar 

  123. Bhatia M, Bonnet D, Murdoch B, et al. A newly discovered class of human hematopoietic cells with SCID-repopulating activity. Nat Med. 1998;4:1038-1045.

    CAS  PubMed  Google Scholar 

  124. Bhatia M, Wang JC, Kapp U, et al. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci USA. 1997;94:5320-5325.

    CAS  PubMed  Google Scholar 

  125. Wulf-Goldenberg A, Eckert K, Fichtner I. Cytokine-pretreatment of CD34+ cord blood stem cells in vitro reduces long-term cell engraftment in NOD/SCID mice. Eur J Cell Biol. 2008;87:69-80.

    CAS  PubMed  Google Scholar 

  126. Jacobsen SE, Borge OJ, Ramsfjell V, et al. Thrombopoietin, a direct stimulator of viability and multilineage growth of primitive bone marrow progenitor cells. Stem Cells. 1996;14(suppl 1):173-180.

    PubMed  Google Scholar 

  127. Kimura S, Roberts AW, Metcalf D, et al. Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc Natl Acad Sci USA. 1998;95:1195-1200.

    CAS  PubMed  Google Scholar 

  128. Borge OJ, Ramsfjell V, Veiby OP, et al. Thrombopoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro. Blood. 1996;88:2859-2870.

    CAS  PubMed  Google Scholar 

  129. Zhang CC, Kaba M, Iizuka S, et al. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood. 2008;111:3415-3423.

    CAS  PubMed  Google Scholar 

  130. Hutton JF, Rozenkov V, Khor FSL, et al. Bone morphogenetic protein 4 contributes to the maintenance of primitive cord blood hematopoietic progenitors in an ex vivo stroma-noncontact co-culture system. Stem Cells Dev. 2006;15:805-813.

    CAS  PubMed  Google Scholar 

  131. Rizo A, Dontje B, Vellenga E, et al. Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1. Blood. 2008;111:2621-2630.

    CAS  PubMed  Google Scholar 

  132. Tanaka H, Matsumura I, Itoh K, et al. HOX decoy peptide enhances the ex vivo expansion of human umbilical cord blood CD34+ hematopoietic stem cells/hematopoietic progenitor cells. Stem Cells. 2006;24:2592-2602.

    CAS  PubMed  Google Scholar 

  133. Nikopoulos GN, Duarte M, Kubu CJ, et al. Soluble jagged1 attenuates lateral inhibition, allowing for the clonal expansion of neural crest stem cells. Stem Cells. 2007;25:3133-3142.

    CAS  PubMed  Google Scholar 

  134. Li K, Ooi VE, Chuen CK, et al. The plant mannose-binding lectin NTL preserves cord blood haematopoietic stem/progenitor cells in long-term culture and enhances their ex vivo expansion. Br J Haematol. 2008;140:90-98.

    CAS  PubMed  Google Scholar 

  135. Prus E, Fibach E. The effect of the copper chelator tetraethylenepentamine on reactive oxygen species generation by human hematopoietic progenitor cells. Stem Cells Dev. 2007;16:1053-1056.

    CAS  PubMed  Google Scholar 

  136. de Lima M, McMannis J, Gee A, et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I//II clinical trial. Bone Marrow Transplant. 2008;41:771-778.

    PubMed  Google Scholar 

  137. Harrison DE, Stone M, Astle CM. Effects of transplantation on the primitive immunohematopoietic stem cell. J Exp Med. 1990;172:431-437.

    CAS  PubMed  Google Scholar 

  138. Fraser CC, Eaves CJ, Szilvassy SJ, et al. Expansion in vitro of retrovirally marked totipotent hematopoietic stem cells. Blood. 1990;76:1071-1076.

    CAS  PubMed  Google Scholar 

  139. Glimm H, Eaves CJ. Direct evidence for multiple self-renewal divisions of human in vivo repopulating hematopoietic cells in short-term culture. Blood. 1999;94:2161-2168.

    CAS  PubMed  Google Scholar 

  140. Miller CL, Eaves CJ. Expansion in vitro of adult murine hematopoietic stem cells with transplantable lympho-myeloid reconstituting ability. Proc Natl Acad Sci USA. 1997;94:13648-13653.

    CAS  PubMed  Google Scholar 

  141. Ema H, Takano H, Sudo K, et al. In vitro self-renewal division of hematopoietic stem cells. J Exp Med. 2000;192:1281-1288.

    CAS  PubMed  Google Scholar 

  142. Yagi M, Ritchie KA, Sitnicka E, et al. Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin. Proc Natl Acad Sci USA. 1999;96:8126-8131.

    CAS  PubMed  Google Scholar 

  143. Bryder D, Jacobsen SE. Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro. Blood. 2000;96:1748-1755.

    CAS  PubMed  Google Scholar 

  144. Jiang X-S, Chai C, Zhang Y, et al. Surface-immobilization of adhesion peptides on substrate for ex vivo expansion of cryopreserved umbilical cord blood CD34+ cells. Biomaterials. 2006;27:2723-2732.

    CAS  PubMed  Google Scholar 

  145. Iwama A, Oguro H, Negishi M, et al. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity. 2004;21:843-851.

    CAS  PubMed  Google Scholar 

  146. Williams DA, Baum C. Medicine. Gene therapy – new challenges ahead. Science. 2003;302:400-401.

    CAS  PubMed  Google Scholar 

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Gao, JX., Zhou, Q. (2011). Cord Blood Stem Cell Expansion Ex Vivo: Current Status and Future Strategies. In: Bhattacharya, N., Stubblefield, P. (eds) Regenerative Medicine Using Pregnancy-Specific Biological Substances. Springer, London. https://doi.org/10.1007/978-1-84882-718-9_26

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