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Hematopoietic stem cells for transplantation

Nature Immunology volume 3, pages 314317 (2002) | Download Citation

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Multiple sources of HSCs exist. Here, Verfaillie discusses the long-term engraftment capabilities of each source and the search for ex vivo expansion conditions to allow bulk culture for therapeutic HSC transplantation.

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References

  1. 1.

    et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nature Med. 2, 1329–1337 (1996).

  2. 2.

    et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood 95, 952–928 (2000).

  3. 3.

    et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964–967 (1997).

  4. 4.

    , , , & Characterization and partial purification of human marrow cells capable of initiating long-term hematopoiesis in vitro. Blood 74, 1563–1570 (1989).

  5. 5.

    et al. Transplantation with selected autologous peripheral blood CD34+Thy1+ hematopoietic stem cells (HSCs) in multiple myeloma: impact of HSC dose on engraftment, safety, and immune reconstitution. Exp. Hematol. 28, 858–870 (2000).

  6. 6.

    et al. CD34+ human marrow cells that express low levels of Kit protein are enriched for long-term marrow-engrafting cells. Blood 87, 4136–4142 (1996).

  7. 7.

    , , & Long-term lymphohematopoietic reconstitution by a single 34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).

  8. 8.

    , & Reversible expression of CD34 by murine hematopoietic stem cells. Blood 94, 2548–5254 (1999).

  9. 9.

    , & Developmental changes of CD34 expression by murine hematopoietic stem cells. Exp. Hematol. 28,1269–1273 (2001).

  10. 10.

    , , , & A newly discovered class of human hematopoietic cells with SCID-repopulating activity. Nature Med. 4, 1038–1045 (1998).

  11. 11.

    et al. Ex vivo generation of CD34+ cells from CD34 hematopoietic cells. Blood. 94, 4053–4059 (1999).

  12. 12.

    , , & Kinetics of engraftment of CD34 and CD34+ cells from mobilized blood differs from that of CD34 and CD34+ cells from bone marrow. Exp. Hematol. 28, 1071–1079 (2000).

  13. 13.

    et al. Absence of a CD34 hematopoietic precursor population in recipients of CD34+ stem cell transplantation. Bone Marrow Transplant. 28, 587–595 (2001).

  14. 14.

    et al. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90, 5002–5012 (1997).

  15. 15.

    , , , & Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183, 1797–1806 (1996).

  16. 16.

    et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Med. 7, 1028–1034 (2001).

  17. 17.

    , , & Transplantable hematopoietic stem cells in human fetal liver have a CD34+ side population (SP)phenotype. J. Clin. Invest. 108, 1071–1077 (2001).

  18. 18.

    , , , & Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc. Natl Acad. Sci. USA 94, 5320 (1997).

  19. 19.

    et al. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse as a model system to study the engraftment and mobilization of human peripheral blood stem cells. Blood 92, 2556–2570 (1998).

  20. 20.

    et al. Partially differentiated ex vivo expanded cells accelerate hematologic recovery in myeloablated mice transplanted with highly enriched long-term repopulating stem cells. Blood 88, 3642–3653 (1996).

  21. 21.

    , & Bone marrow transplantation with interleukin-1 plus kit-ligand ex vivo expanded bone marrow accelerates hematopoietic reconstitution in mice without the loss of stem cell lineage and proliferative potential. Blood 81, 3463–3473 (1993).

  22. 22.

    , , & Ex vivo expansion of murine marrow cells with interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor leads to impaired engraftment in irradiated hosts. Blood 87, 30–37 (1996).

  23. 23.

    & Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood 95, 2284–2288 (2000).

  24. 24.

    , , , & Quantitative assay for totipotent reconstituting hematopoietic stem cells by a competitive repopulation strategy. Proc. Natl Acad. Sci. USA 87, 8736–8740 (1990).

  25. 25.

    , , , & Extended long-term culture reveals a highly quiescent and primitive human hematopoietic progenitor population. Blood 88, 3306–3313 (1996).

  26. 26.

    et al. The myeloid-lymphoid initiating cell (ML-IC) assay assesses the fate of multipotent human progenitors in vitro. Blood 93, 3750–3756 (1999).

  27. 27.

    , , , & Identification of human T-lymphoid progenitor cells in CD34+ CD38low and CD34+ CD38+ subsets of human cord blood and bone marrow cells using NOD-SCID fetal thymus organ cultures. Br. J. Haematol. 104, 809–819 (1999).

  28. 28.

    , , & Culture of phenotypically defined hematopoietic stem cells and other progenitors at limiting dilution on Dexter monolayers. Blood 78, 945–952 (1991).

  29. 29.

    , & Sustained human hematopoiesis in immunodeficient mice by cotransplantation of marrow stroma expressing human interleukin-3: analysis of gene transduction of long-lived progenitors. Blood 83, 3041–3051 (1994).

  30. 30.

    et al. Sustained, retransplantable, multilineage engraftment of highly purified adult human bone marrow stem cells in vivo. Blood 88, 4102–4109 (1996).

  31. 31.

    et al. β2 microglobulin-deficient (B2mnull) NOD/SCID mice are excellent recipients for studying human stem cell function. Blood 95, 3102–3105 (2000).

  32. 32.

    , , & An in vivo competitive repopulation assay for various sources of human hematopoietic stem cells. Blood 96, 3414–3421 (2000).

  33. 33.

    et al. Previously undetected human hematopoietic cell populations with short-term repopulating activity selectively engraft NOD/SCID-β2 microglobulin-null mice. J. Clin. Invest. 107, 199–206 (2001).

  34. 34.

    et al. Long-term persistence of canine hematopoietic cells genetically marked by retrovirus vectors. Hum. Gene Ther. 7, 89–96 (1996).

  35. 35.

    & Update on the use of nonhuman primate models for preclinical testing of gene therapy approaches targeting hematopoietic cells. Hum. Gene Ther. 10, 607–617 (2001).

  36. 36.

    , , & The repopulation potential of fetal liver hematopoietic stem cells in mice exceeds that of their liver adult bone marrow counterparts. Blood 87, 3500–3507 (1996).

  37. 37.

    , , & Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. Blood 98, 2108–2115 (2001).

  38. 38.

    , , & Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med. 192, 1273–1280 (2000).

  39. 39.

    , , & In vitro self-renewal division of hematopoietic stem cells. J. Exp. Med. 192, 1281–1288 (2000).

  40. 40.

    , & Functional differences between transplantable human hematopoietic stem cells from fetal liver, cord blood, and adult marrow. Exp. Hematol. 27, 1418–1427 (1999).

  41. 41.

    & The aging of lympho-hematopoietic stem cells. Nature Immunol. 3, 329–333 (2002).

  42. 42.

    & Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood 98, 2900–2908 (2001).

  43. 43.

    , & Phenotypic and functional characterization of long-term culture-initiating cells present in peripheral blood progenitor collections of normal donors treated with granulocyte colony-stimulating factor. Blood 88, 2033–2042 (1996).

  44. 44.

    et al. Characterization of primitive hematopoietic cells in normal human peripheral blood. Blood 80, 2513–2522 (1993).

  45. 45.

    et al. Accelerated telomere shortening following allogeneic transplantation is independent of the cell source and occurs within the first year post transplant. Bone Marrow Transplant. 27, 1283–1286 (2001).

  46. 46.

    et al. Improved retroviral gene transfer into murine and Rhesus peripheral blood or bone marrow repopulating cells primed in vivo with stem cell factor and granulocyte colony-stimulating factor. Proc. Natl Acad. Sci. USA 93, 11871–11876 (1996).

  47. 47.

    , , , & Steel factor influences the distribution and activity of murine hematopoietic stem cells in vivo. Proc. Natl Acad. Sci. USA 90, 3760–3764 (1993).

  48. 48.

    et al. Effects of granulocyte colony-stimulating factor and stem cell factor, alone and in combination, on the mobilization of peripheral blood cells that engraft lethally irradiated dogs. Blood 83, 3795–3802 (1994).

  49. 49.

    et al. Rapid engraftment by peripheral blood progenitor cells mobilized by recombinant human stem cell factor and recombinant human granulocyte colony-stimulating factor in nonhuman primates. Blood 85, 1995–2006 (1995).

  50. 50.

    et al. Peripheral blood progenitor cell mobilization using stem cell factor in combination with filgrastim in breast cancer patients. Blood 90, 2939–2951 (1997).

  51. 51.

    et al. Expansion in bioreactors of human progenitor populations from cord blood and mobilized peripheral blood. Blood Cells 20, 482–490 (1994).

  52. 52.

    , , , & Reconstitution of hematopoiesis after high-dose chemotherapy by autologous progenitor cells generated ex vivo. N. Engl. J. Med. 333, 283–287 (1995).

  53. 53.

    et al. Autologous transplantation of ex vivo expanded bone marrow cells grown from small aliquots after high-dose chemotherapy for breast cancer. Blood 95, 2169–2174 (2000).

  54. 54.

    et al. Ex vivo expanded peripheral blood progenitor cells provide rapid neutrophil recovery after high-dose chemotherapy in patients with breast cancer. Blood 96, 3001–3007 (2000).

  55. 55.

    et al. Abrogation of post-myeloablative chemotherapy neutropenia by ex-vivo expanded autologousCD34-positive cells. Lancet 354, 1092–1093 (1999).

  56. 56.

    & Ex vivo expansion of hematopoietic progenitor cells and mature cells. Exp. Hematol. 29, 3–11 (2001).

  57. 57.

    et al. Ex-vivo expansion of hematopoietic progenitor cells: preliminary results in breast cancer. Hematol. Cell Ther. 41, 82–86 (1999).

  58. 58.

    et al. Megakaryocytic progenitors can be generated ex vivo and safely administered to autologous peripheral blood progenitor cell transplant recipients. Blood 89, 2679–2688 (1997).

  59. 59.

    et al. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic progenitors. Blood 91, 2588–2600 (1999).

  60. 60.

    et al. CD34 positive PBPC expanded ex vivo may not provide durable engraftment following myeloablative chemoradiotherapy regimens. Bone Marrow Transplant. 19, 1095–1101 (1997).

  61. 61.

    , , , & Functional heterogeneity of human CD34+ cells isolated in subcompartments of the G0 /G1 phase of the cell cycle. Blood 90, 4384–4393 (1997).

  62. 62.

    et al. The fluctuating phenotype of the lymphohematopoietic stem cell with cell cycle transit. J. Exp. Med. 188, 393–398 (1998).

  63. 63.

    , , & Cell cycle activation of hematopoietic progenitor cells increases very lateantigen-5-mediated adhesion to fibronectin. Exp. Hematol., 29, 515–524 (2001).

  64. 64.

    , & Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G2/M transit and do not reenter G0. Blood 96, 4185–4193 (2000).

  65. 65.

    et al. Homing and engraftment potential of Sca-1+lin cells fractionated on the basis of adhesion molecule expression and position in cell cycle. Blood 96, 1380–1387 (2000).

  66. 66.

    et al. In vitro expansion of hematopoietic progenitor cells induces functional expression of Fas antigen (CD95). Blood 88, 2871–2877 (1996).

  67. 67.

    , & 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. 191, 253–264 (2000).

  68. 68.

    , , , & Expression and activation of caspase-3/CPP32 in CD34+ cord blood cells is linked to apoptosis after growth factor withdrawal. Exp. Hematol. 28, 907–915 (2000).

  69. 69.

    Stochastic model revisited. Int. J. Hematol. 69, 2–5 (1999).

  70. 70.

    et al. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 9, 1753–1765 (1995).

  71. 71.

    , & HOXB4 overexpression mediates very rapid stem cell regeneration and competitive hematopoietic repopulation. Exp. Hematol. 29, 1125–1134 (2001).

  72. 72.

    et al. Hematopoietic stem cell maintenance and differentiation are supported by embryonic aorta-gonad-mesonephros region-derived endothelium. Blood 92, 908 (1998).

  73. 73.

    , , & Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells. Blood 87, 4082–4090 (1996).

  74. 74.

    & A stromal cell line from myeloid long-term bone marrow cultures can support myelopoiesis and B lymphopoiesis. J. Immunol. 15, 1082–1087 (1987).

  75. 75.

    et al. Reproducible establishment of hemopoietic supportive stromal cell lines from murine bone marrow. Exp. Hematol. 17, 145–153 (1998).

  76. 76.

    Microenvironmental regulation of hematopoietic stem cells. Stem Cells 15, 63–68 (1997).

  77. 77.

    et al. The human homologue of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity 8, 43–55 (1998).

  78. 78.

    et al. Quantitative analysis reveals expansion of human hematopoietic repopulating cells after short-term ex vivo culture. J. Exp. Med. 186, 619–624 (1997).

  79. 79.

    , , & 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 94, 9836 (1997).

  80. 80.

    et al. Engraftment in nonobese diabetic severe combined immunodeficient mice of human CD34+ cord blood cells after ex vivo expansion: evidence for the amplification and self-renewal of repopulating stem cells. Blood 93, 3736–3749 (1999).

  81. 81.

    et al. The soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro maintenance and proliferation of human CD34+CD38−/low cells capable of repopulating severe combined immunodeficiency mice. Blood 94, 923–931 (1999).

  82. 82.

    et al. Ex vivo expansion of genetically marked rhesus peripheral blood progenitor cells results in diminished long-term repopulating ability. Blood 92, 1131–1141 (1998).

  83. 83.

    , , & Adhesion to fibronectin maintains regenerative capacity during ex vivo culture and transduction of human hematopoietic stem and progenitor cells. Blood 92, 4612–4621 (1998).

  84. 84.

    , & Direct adhesion to bone marrow stroma via fibronectin receptors inhibits hematopoietic progenitor proliferation. J. Clin. Invest. 96, 511–512 (1995).

  85. 85.

    , , & Marrow-derived heparan sulfate proteoglycan mediates the adhesion of hematopoietic progenitor cells to cytokines. Exp. Hematol. 23, 1212–1217 (1995).

  86. 86.

    et al. Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis. Nature 332, 376 (1988).

  87. 87.

    et al. Structurally specific heparan sulfates support primitive human hematopoiesis by formation of a multimolecular stem cell niche. 92, 4641–4651 (1998).

  88. 88.

    et al. Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells. J. Exp. Med. 189, 1139–1148 (1999).

  89. 89.

    , , , & Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 128, 1717–1730 (2001).

  90. 90.

    LIN-12/Notch signaling: lessons from worms and flies. Genes Dev. 12, 1751–1762 (1998).

  91. 91.

    et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J. Exp. Med. 192, 1365–1372 (2000).

  92. 92.

    et al. The Notch ligand Jagged-1 influences the development of primitive hematopoietic precursor cells. Blood 91, 4084 (1998).

  93. 93.

    , , , & Hematopoietic activity of a stromal cell transmembrane protein containing epidermal growth factor-like repeat motifs. Proc. Natl Acad. Sci. USA 94, 4011 (1997).

  94. 94.

    et al. The genetic program of hematopoietic stem cells. Science 288, 1635–1640 (2000).

  95. 95.

    et al. From hematopoiesis to neuropoiesis: evidence of overlapping genetic programs. Proc. Natl Acad. Sci. USA 98, 7934–7939 (2001).

  96. 96.

    Multilineage development from adult bone marrow cells. Nature Immunol. 3, 311–313 (2002).

  97. 97.

    & Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nature Immunol. 3, 323–328 (2002).

  98. 98.

    , , , & Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 283, 354–357 (1999).

  99. 99.

    et al. Identification of a candidate human neurohematopoietic stem-cell population. Blood 98, 2412–2422 (2001).

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  1. Division of Hematology, Department of Medicine, and Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA. verfa001@tc.umn.edu

    • Catherine M. Verfaillie

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https://doi.org/10.1038/ni0402-314

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