Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 141 No. 5152 (2011)

Ex vivo expansion of hematopoietic stem cells: mission accomplished?

  • H Takizawa
  • MG Manz
DOI
https://doi.org/10.4414/smw.2011.13316
Cite this as:
Swiss Med Wkly. 2011;141:w13316
Published
19.12.2011

Summary

A small number of hematopoietic stem cells (HSCs) with self-renewal and multi-lineage repopulation capacity maintain hematopoiesis during the lifetime of an individual. Moreover, HSCs and their potential exist in excess as one individual can share its HSCs with another leading to creation of a genetically identical hematopoietic system. For over half a century this property of HSCs has been utilised by successful allogeneic clinical HSC transplantation for treatment of patients with inherited or acquired genetic and neoplastic diseases of the hematopoietic and immune system. There are now more than twenty thousand allogeneic HSC transplants per year worldwide [1]. However, although more than 17.5 million potential HSC donors are registered and additional 500,000 cord bloods are stored for potential allogeneic HSC transplantation [2], timely availability of appropriately human leukocyte antigen (HLA)-compatible HSCs with sufficient quality for patients still poses a problem in the field. Even if a donor is available, toxicity of the procedure could be reduced by increasing HSC numbers in transplants. One way to solve these issues would be by generation of quality-controlled, off the shelf HSC products via in vitro HSC expansion, a “holy grail” procedure many have been hunting for. Here, we discuss accumulating knowledge on signalling pathways involved in HSC maintenance as well as recent achievements to apply the findings to ex vivo HSC expansion for clinical use. Although the specific issue concerns only highly specialised medicine today, newly generated knowledge will be critical for the whole field of stem cell transplantation and regenerative medicine in the future.

References

  1. Gratwohl A, Baldomero H, Aljurf M, Pasquini MC, Bouzas LF, Yoshimi A, et al. Hematopoietic Stem Cell Transplantation A Global Perspective. Jama-J Am Med Assoc. 2010;303:1617–24.
  2. Champlin R. Now everyone has a donor for HSCT. Blood. 2011;118:218.
  3. Gordon MY, Lewis JL, Marley SB. Of mice and men... and elephants. Blood. 2002;100:4679–80.
  4. Kiel MJ, Morrison SJ. Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol. 2008;8:290–301.
  5. Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 2009;457:92–6.
  6. Xie Y, Yin T, Wiegraebe W, He XC, Miller D, Stark D, et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature. 2009;457:97–101.
  7. Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol. 2003;21:759–806.
  8. Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood. 2003;102:517–20.
  9. Dick JE, Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333:218–21.
  10. Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121:1109–21.
  11. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996;273:242–5.
  12. Takizawa H, Regoes RR, Boddupalli CS, Bonhoeffer S, Manz MG. Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation. J Exp Med. 2011.
  13. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6:93–106.
  14. Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med. 2007;357:1472–5.
  15. Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL. Physiological migration of hematopoietic stem and progenitor cells. Science. 2001;294:1933–6.
  16. Appelbaum FR. Hematopoietic cell transplantation from unrelated donors for treatment of patients with acute myeloid leukemia in first complete remission. Best Pract Res Clin Haematol. 2007;20:67–75.
  17. Krenger W, Hollander GA. The role of the thymus in allogeneic hematopoietic stem cell transplantation. Swiss Med Wkly. 2010;140:w13051.
  18. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091–101.
  19. Passweg J, Baldomero H, Stern M, Bargetzi M, Ghielmini M, Leibundgut K, et al. Hematopoietic stem cell transplantation in Switzerland: a comprehensive quality control report on centre effect. Swiss Med Wkly. 2010;140:326–34.
  20. To LB, Haylock DN, Simmons PJ, Juttner CA. The biology and clinical uses of blood stem cells. Blood. 1997;89:2233–58.
  21. Gluckman E. Milestones in umbilical cord blood transplantation. Blood Rev. 2011.
  22. Thomson BG, Robertson KA, Gowan D, Heilman D, Broxmeyer HE, Emanuel D, et al. Analysis of engraftment, graft-versus-host disease, and immune recovery following unrelated donor cord blood transplantation. Blood. 2000;96:2703–11.
  23. Wagner JE, Rosenthal J, Sweetman R, Shu XO, Davies SM, Ramsay NK, McGlave PB, et al. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood. 1996;88:795–802.
  24. Sideri A, Neokleous N, Brunet de la Grange P, Guerton B, Le Bousse Kerdiles MC, Uzan G, et al. An overview of the progress on double umbilical cord blood transplantation. Haematologica. 2011.
  25. Chen YB, Spitzer TR. Current status of reduced-intensity allogeneic stem cell transplantation using alternative donors. Leukemia. 2008;22:31–41.
  26. Rubinstein P, Dobrila L, Rosenfield RE, Adamson JW, Migliaccio G, Migliaccio AR, et al. Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc Natl Acad Sci U S A 1995;92:10119–22.
  27. McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68:283–302.
  28. Sauvageau G, Thorsteinsdottir U, Eaves CJ, Lawrence HJ, Largman C, Lansdorp PM, et al. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 1995;9:1753–65.
  29. Antonchuk J, Sauvageau G, Humphries RK. HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell. 2002;109:39–45.
  30. Sauvageau G, Iscove NN, Humphries RK. In vitro and in vivo expansion of hematopoietic stem cells. Oncogene. 2004;23:7223–32.
  31. Brun AC, Bjornsson JM, Magnusson M, Larsson N, Leveen P, Ehinger M, Nilsson E, Karlsson S. Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells. Blood 2004; 103:4126-33.
  32. Baum C, von Kalle C, Staal FJ, Li Z, Fehse B, Schmidt M, et al. Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther. 2004;9:5–13.
  33. Krosl J, Austin P, Beslu N, Kroon E, Humphries RK, Sauvageau G. In vitro expansion of hematopoietic stem cells by recombinant TAT-HOXB4 protein. Nat Med. 2003;9:1428–32.
  34. Amsellem S, Pflumio F, Bardinet D, Izac B, Charneau P, Romeo PH, et al. Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Nat Med. 2003;9:1423–7.
  35. Rennick DM, Lee FD, Yokota T, Arai KI, Cantor H, Nabel GJ. A cloned MCGF cDNA encodes a multilineage hematopoietic growth factor: multiple activities of interleukin 3. J Immunol. 1985;134:910–4.
  36. Bhatia M, Bonnet D, Kapp U, Wang JC, Murdoch B, Dick JE. Quantitative analysis reveals expansion of human hematopoietic repopulating cells after short-term ex vivo culture. J Exp Med. 1997;186:619–24.
  37. Ema H, Takano H, Sudo K, Nakauchi H. In vitro self-renewal division of hematopoietic stem cells. J Exp Med. 2000;192:1281–8.
  38. Varnum-Finney B, Brashem-Stein C, Bernstein ID. Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability. Blood. 2003;101:1784–9.
  39. Lemieux ME, Chappel SM, Miller CL, Eaves CJ. Differential ability of flt3-ligand, interleukin-11, and Steel factor to support the generation of B cell progenitors and myeloid cells from primitive murine fetal liver cells. Exp Hematol. 1997;25:951–7.
  40. Miller CL, Eaves CJ. Expansion in vitro of adult murine hematopoietic stem cells with transplantable lympho-myeloid reconstituting ability. Proc Natl Acad Sci. U S A 1997;94:13648–53.
  41. Brandt J, Briddell RA, Srour EF, Leemhuis TB, Hoffman R. Role of c-kit ligand in the expansion of human hematopoietic progenitor cells. Blood. 1992;79:634–41.
  42. de Haan G, Weersing E, Dontje B, van Os R, Bystrykh LV, Vellenga E, et al. In vitro generation of long-term repopulating hematopoietic stem cells by fibroblast growth factor-1. Dev Cell. 2003;4:241–51.
  43. Nakamura Y, Yahata T, Muguruma Y, Uno T, Sato T, Matsuzawa H, et al. Angiopoietin-1 supports induction of hematopoietic activity in human CD34- bone marrow cells. Exp Hematol. 2007;35:1872–83.
  44. Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, et al. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med. 2010;16:475–82.
  45. Zhang CC, Kaba M, Ge G, Xie K, Tong W, Hug C, et al. Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nat Med. 2006;12:240–5.
  46. Kojika S, Griffin JD. Notch receptors and hematopoiesis. Exp Hematol. 2001;29:1041–52.
  47. Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M, Sakano S, et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med. 2000;192:1365–72.
  48. Pereira RMR, Delany AM, Durant D, Canalis E. Cortisol regulates the expression of Notch in osteoblasts. J Cell Biochem. 2002;85:252–8.
  49. Mancini SJ, Mantei N, Dumortier A, Suter U, MacDonald HR, Radtke F. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood. 2005;105:2340–2.
  50. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003; 425:836-41.
  51. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–6.
  52. Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S, et al. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med. 2000;6:1278–81.
  53. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010;16:232–6.
  54. Ohishi K, Varnum-Finney B, Bernstein ID. Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(-) cord blood cells. J Clin Invest. 2002;110:1165–74.
  55. Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287:795–801.
  56. Detmer K, Walker AN, Jenkins TM, Steele TA, Dannawi H. Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of hedgehog signaling. Blood Cells Mol Dis. 2000;26:360–72.
  57. Outram SV, Varas A, Pepicelli CV, Crompton T. Hedgehog signaling regulates differentiation from double-negative to double-positive thymocyte. Immunity. 2000;13:187–97.
  58. Dyer MA, Farrington SM, Mohn D, Munday JR, Baron MH. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development. 2001;128:1717–30.
  59. Gao J, Graves S, Koch U, Liu S, Jankovic V, Buonamici S, et al. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell. 2009;4:548–58.
  60. Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol. 2001;2:172–80.
  61. Bhatia M, Bonnet D, Wu D, Murdoch B, Wrana J, Gallacher L, et al. Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells. J Exp Med. 1999;189:1139–48.
  62. Austin TW, Solar GP, Ziegler FC, Liem L, Matthews W. A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells. Blood. 1997;89:3624–35.
  63. Van Den Berg DJ, Sharma AK, Bruno E, Hoffman R. Role of members of the Wnt gene family in human hematopoiesis. Blood. 1998;92:3189–202.
  64. Murdoch B, Chadwick K, Martin M, Shojaei F, Shah KV, Gallacher L, et al. Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc Natl Acad Sci. U S A 2003;100:3422–7.
  65. Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423:409–14.
  66. Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423:448–52.
  67. Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol. 2006;7:1048–56.
  68. Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, et al. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol. 2006;7:1037–47.
  69. Cobas M, Wilson A, Ernst B, Mancini SJ, MacDonald HR, Kemler R, et al. Beta-catenin is dispensable for hematopoiesis and lymphopoiesis. J Exp Med. 2004;199:221–9.
  70. Koch U, Wilson A, Cobas M, Kemler R, Macdonald HR, Radtke F. Simultaneous loss of beta- and gamma-catenin does not perturb hematopoiesis or lymphopoiesis. Blood. 2008;111:160–4.
  71. Nemeth MJ, Topol L, Anderson SM, Yang Y, Bodine DM. Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc Natl Acad Sci. U S A 2007;104:15436–41.
  72. Trowbridge JJ, Xenocostas A, Moon RT, Bhatia M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med. 2006;12:89–98.
  73. Bertrand JY, Traver D. Hematopoietic cell development in the zebrafish embryo. Curr Opin Hematol. 2009;16:243–8.
  74. North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447:1007–11.
  75. Miller SB. Prostaglandins in health and disease: an overview. Semin Arthritis Rheum. 2006;36:37–49.
  76. Lorenz M, Slaughter HS, Wescott DM, Carter SI, Schnyder B, Dinchuk JE, et al. Cyclooxygenase-2 (COX-2) is essential for normal recovery from 5-fluorouracil (5-FU) induced myelotoxicity in mice. Blood. 1996;88:1358–8.
  77. Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood. 2009;113:5444–55.
  78. Goessling W, North TE, Loewer S, Lord AM, Lee S, Stoick-Cooper CL, et al. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell. 2009;136:1136–47.
  79. Frisch BJ, Porter RL, Gigliotti BJ, Olm-Shipman AJ, Weber JM, O’Keefe RJ, et al. In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells. Blood. 2009;114:4054–63.
  80. Durand EM, Zon LI. Newly emerging roles for prostaglandin E2 regulation of hematopoiesis and hematopoietic stem cell engraftment. Curr Opin Hematol. 2010;17:308–12.
  81. Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science. 2010;329:1345–8.
  82. de Wynter EA, Buck D, Hart C, Heywood R, Coutinho LH, Clayton A, et al. CD34+AC133+ cells isolated from cord blood are highly enriched in long-term culture-initiating cells, NOD/SCID-repopulating cells and dendritic cell progenitors. Stem Cells. 1998;16:387–96.
  83. Singh KP, Casado FL, Opanashuk LA, Gasiewicz TA. The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations. Biochem Pharmacol. 2009;77:577–87.
  84. Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135:1118–29.
  85. Foudi A, Hochedlinger K, Van Buren D, Schindler JW, Jaenisch R, Carey V, et al. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat Biotechnol. 2009;27:84–90.
  86. 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;192:1707–18.
  87. Dellatore SM, Garcia AS, Miller WM. Mimicking stem cell niches to increase stem cell expansion. Curr Opin Biotechnol. 2008;19:534–40.
  88. Kobune M, Kawano Y, Kato J, Ito Y, Chiba H, Nakamura K, et al. Expansion of CD34+ cells on telomerized human stromal cells without losing erythroid-differentiation potential in a serum-free condition. Int J Hematol. 2005;81:18–25.
  89. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–41.
  90. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31:890–6.
  91. McNiece I, Harrington J, Turney J, Kellner J, Shpall EJ. Ex vivo expansion of cord blood mononuclear cells on mesenchymal stem cells. Cytotherapy. 2004;6:311–7.
  92. Kelly SS, Sola CB, de Lima M, Shpall E. Ex vivo expansion of cord blood. Bone Marrow Transplant. 2009;44:673–81.
  93. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.
  94. Manz MG. Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity. 2007;26:537–41.
  95. O’Connell RM, Balazs AB, Rao DS, Kivork C, Yang L, Baltimore D. Lentiviral vector delivery of human interleukin-7 (hIL-7) to human immune system (HIS) mice expands T lymphocyte populations. PLoS One. 2010;5:e12009.
  96. Huntington ND, Legrand N, Alves NL, Jaron B, Weijer K, Plet A, et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med. 2009;206:25–34.
  97. van Lent AU, Dontje W, Nagasawa M, Siamari R, Bakker AQ, Pouw SM, et al. IL-7 enhances thymic human T cell development in “human immune system” Rag2-/-IL-2Rgammac-/- mice without affecting peripheral T cell homeostasis. J Immunol. 2009;183:7645–55.
  98. Billerbeck E, Barry WT, Mu K, Dorner M, Rice CM, Ploss A. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor, GM-CSF and interleukin 3 expressing NOD SCID IL2R{gamma}NULL humanized mice. Blood. 2011.
  99. Willinger T, Rongvaux A, Takizawa H, Yancopoulos GD, Valenzuela DM, Murphy AJ, et al. Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc Natl Acad Sci. U S A 2011;108:2390–5.
  100. Rongvaux A, Willinger T, Takizawa H, Rathinam C, Auerbach W, Murphy AJ, et al. Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo. Proc Natl Acad Sci. U S A 2011;108:2378–83.
  101. Willinger T, Rongvaux A, Strowig T, Manz MG, Flavell RA. Improving human hemato-lymphoid-system mice by cytokine knock-in gene replacement. Trends Immunol. 2011;32:321–7.