Advertisement

Recapitulating Hematopoietic Development in a Dish

  • Kim Vanuytsel
  • Martin H. Steinberg
  • George J. MurphyEmail author
Chapter
Part of the Current Human Cell Research and Applications book series (CHCRA)

Abstract

The ability to generate patient-specific, induced pluripotent stem cells (iPSCs) together with the advent of gene-editing technologies has opened up a realm of opportunities for disease modeling, gene correction, and regenerative medicine applications aimed at better understanding and treating hematological disorders. The widespread use of reprogramming and gene-editing techniques has resulted in fine-tuning of these technologies to the point where they are an integral part of molecular biology research toolkits. The challenge remaining at this point is to achieve efficient and robust differentiation of pluripotent stem cells (PSCs) toward blood cells that resemble their in vivo counterparts. Here we provide an overview of our current understanding of in vivo hematopoietic development and how that has been used as a roadmap to guide in vitro hematopoietic development. We discuss recent advances and limitations encountered when recapitulating hematopoietic development in vitro. Finally, we highlight examples of how patient-specific iPSCs have been successfully used for the modeling of hematological disorders and how they have played a prominent role in uncovering pharmacologically targetable disease mechanisms.

Keywords

Pluripotent stem cells iPSCs Hematopoietic stem cell Hematopoiesis Erythropoiesis Disease modeling Hemoglobinopathies 

References

  1. 1.
    Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132:631–44.  https://doi.org/10.1016/j.cell.2008.01.025.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Vo LT, Daley GQ. De novo generation of HSCs from somatic and pluripotent stem cell sources. Blood. 2015;125:2641–8.  https://doi.org/10.1182/blood-2014-10-570234.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Tavian M, Peault B. Embryonic development of the human hematopoietic system. Int J Dev Biol. 2005;49:243–50.  https://doi.org/10.1387/ijdb.041957mt.CrossRefPubMedGoogle Scholar
  4. 4.
    Ivanovs A, et al. Human haematopoietic stem cell development: from the embryo to the dish. Development. 2017;144:2323–37.  https://doi.org/10.1242/dev.134866.CrossRefPubMedGoogle Scholar
  5. 5.
    Ferkowicz MJ, Yoder MC. Blood island formation: longstanding observations and modern interpretations. Exp Hematol. 2005;33:1041–7.  https://doi.org/10.1016/j.exphem.2005.06.006.CrossRefPubMedGoogle Scholar
  6. 6.
    Palis J, Robertson S, Kennedy M, Wall C, Keller G. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development. 1999;126:5073–84.PubMedGoogle Scholar
  7. 7.
    Wood WG. Haemoglobin synthesis during human fetal development. Br Med Bull. 1976;32:282–7.CrossRefGoogle Scholar
  8. 8.
    Palis J. Primitive and definitive erythropoiesis in mammals. Front Physiol. 2014;5:3.  https://doi.org/10.3389/fphys.2014.00003.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Philipsen S, Wood WG. In: Forget BG, Steinberg MH, Higgs DR, Weatherall DJ, editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management Ch. 2. Cambridge: Cambridge University Press; 2009. p. 24–45.Google Scholar
  10. 10.
    Fraser ST, Isern J, Baron MH. Maturation and enucleation of primitive erythroblasts during mouse embryogenesis is accompanied by changes in cell-surface antigen expression. Blood. 2007;109:343–52.  https://doi.org/10.1182/blood-2006-03-006569.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kingsley PD, Malik J, Fantauzzo KA, Palis J. Yolk sac-derived primitive erythroblasts enucleate during mammalian embryogenesis. Blood. 2004;104:19–25.  https://doi.org/10.1182/blood-2003-12-4162.CrossRefPubMedGoogle Scholar
  12. 12.
    Tober J, et al. The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood. 2007;109:1433–41.  https://doi.org/10.1182/blood-2006-06-031898.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Xu MJ, et al. Evidence for the presence of murine primitive megakaryocytopoiesis in the early yolk sac. Blood. 2001;97:2016–22.CrossRefGoogle Scholar
  14. 14.
    Naito M, Yamamura F, Nishikawa S, Takahashi K. Development, differentiation, and maturation of fetal mouse yolk sac macrophages in cultures. J Leukoc Biol. 1989;46:1–10.CrossRefGoogle Scholar
  15. 15.
    Takahashi K, Yamamura F, Naito M. Differentiation, maturation, and proliferation of macrophages in the mouse yolk sac: a light-microscopic, enzyme-cytochemical, immunohistochemical, and ultrastructural study. J Leukoc Biol. 1989;45:87–96.CrossRefGoogle Scholar
  16. 16.
    Palis J, et al. Spatial and temporal emergence of high proliferative potential hematopoietic precursors during murine embryogenesis. Proc Natl Acad Sci U S A. 2001;98:4528–33.  https://doi.org/10.1073/pnas.071002398.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Nat Rev Mol Cell Biol. 2017;18:56–67.  https://doi.org/10.1038/nrm.2016.127.CrossRefPubMedGoogle Scholar
  18. 18.
    McGrath KE, et al. A transient definitive erythroid lineage with unique regulation of the beta-globin locus in the mammalian embryo. Blood. 2011;117:4600–8.  https://doi.org/10.1182/blood-2010-12-325357.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Migliaccio G, et al. Human embryonic hemopoiesis. Kinetics of progenitors and precursors underlying the yolk sac----liver transition. J Clin Invest. 1986;78:51–60.  https://doi.org/10.1172/JCI112572.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yoshimoto M, et al. Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proc Natl Acad Sci U S A. 2011;108:1468–73.  https://doi.org/10.1073/pnas.1015841108.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Yoshimoto M, et al. Autonomous murine T-cell progenitor production in the extra-embryonic yolk sac before HSC emergence. Blood. 2012;119:5706–14.  https://doi.org/10.1182/blood-2011-12-397489.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Boiers C, et al. Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells. Cell Stem Cell. 2013;13:535–48.  https://doi.org/10.1016/j.stem.2013.08.012.CrossRefPubMedGoogle Scholar
  23. 23.
    Montecino-Rodriguez E, Dorshkind K. B-1 B cell development in the fetus and adult. Immunity. 2012;36:13–21.  https://doi.org/10.1016/j.immuni.2011.11.017.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ginhoux F, Guilliams M. Tissue-resident macrophage ontogeny and homeostasis. Immunity. 2016;44:439–49.  https://doi.org/10.1016/j.immuni.2016.02.024.CrossRefPubMedGoogle Scholar
  25. 25.
    Gomez Perdiguero E, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518:547–51.  https://doi.org/10.1038/nature13989.CrossRefPubMedGoogle Scholar
  26. 26.
    Hoeffel G, et al. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity. 2015;42:665–78.  https://doi.org/10.1016/j.immuni.2015.03.011.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Schulz C, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 2012;336:86–90.  https://doi.org/10.1126/science.1219179.CrossRefPubMedGoogle Scholar
  28. 28.
    Muller AM, Medvinsky A, Strouboulis J, Grosveld F, Dzierzak E. Development of hematopoietic stem cell activity in the mouse embryo. Immunity. 1994;1:291–301.CrossRefGoogle Scholar
  29. 29.
    Medvinsky A, Dzierzak E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell. 1996;86:897–906.CrossRefGoogle Scholar
  30. 30.
    Ivanovs A, et al. Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region. J Exp Med. 2011;208:2417–27.  https://doi.org/10.1084/jem.20111688.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    de Bruijn MF, et al. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta. Immunity. 2002;16:673–83.CrossRefGoogle Scholar
  32. 32.
    de Bruijn MF, Speck NA, Peeters MC, Dzierzak E. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J. 2000;19:2465–74.  https://doi.org/10.1093/emboj/19.11.2465.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gekas C, Dieterlen-Lievre F, Orkin SH, Mikkola HK. The placenta is a niche for hematopoietic stem cells. Dev Cell. 2005;8:365–75.  https://doi.org/10.1016/j.devcel.2004.12.016.CrossRefPubMedGoogle Scholar
  34. 34.
    Ottersbach K, Dzierzak E. The murine placenta contains hematopoietic stem cells within the vascular labyrinth region. Dev Cell. 2005;8:377–87.  https://doi.org/10.1016/j.devcel.2005.02.001.CrossRefPubMedGoogle Scholar
  35. 35.
    Medvinsky A, Rybtsov S, Taoudi S. Embryonic origin of the adult hematopoietic system: advances and questions. Development. 2011;138:1017–31.  https://doi.org/10.1242/dev.040998.CrossRefPubMedGoogle Scholar
  36. 36.
    Charbord P, Tavian M, Humeau L, Peault B. Early ontogeny of the human marrow from long bones: an immunohistochemical study of hematopoiesis and its microenvironment. Blood. 1996;87:4109–19.PubMedGoogle Scholar
  37. 37.
    Blazsek I, Chagraoui J, Peault B. Ontogenic emergence of the hematon, a morphogenetic stromal unit that supports multipotential hematopoietic progenitors in mouse bone marrow. Blood. 2000;96:3763–71.PubMedGoogle Scholar
  38. 38.
    Dzierzak E, Speck NA. Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat Immunol. 2008;9:129–36.  https://doi.org/10.1038/ni1560.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    North TE, et al. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity. 2002;16:661–72.CrossRefGoogle Scholar
  40. 40.
    Taoudi S, Medvinsky A. Functional identification of the hematopoietic stem cell niche in the ventral domain of the embryonic dorsal aorta. Proc Natl Acad Sci U S A. 2007;104:9399–403.  https://doi.org/10.1073/pnas.0700984104.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Boisset JC, et al. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature. 2010;464:116–20.  https://doi.org/10.1038/nature08764.CrossRefPubMedGoogle Scholar
  42. 42.
    Bertrand JY, et al. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature. 2010;464:108–11.  https://doi.org/10.1038/nature08738.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kissa K, Herbomel P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature. 2010;464:112–5.  https://doi.org/10.1038/nature08761.CrossRefPubMedGoogle Scholar
  44. 44.
    Frame JM, Fegan KH, Conway SJ, McGrath KE, Palis J. Definitive hematopoiesis in the yolk sac emerges from Wnt-responsive hemogenic endothelium independently of circulation and arterial identity. Stem Cells. 2016;34:431–44.  https://doi.org/10.1002/stem.2213.CrossRefPubMedGoogle Scholar
  45. 45.
    Samokhvalov IM, Samokhvalova NI, Nishikawa S. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature. 2007;446:1056–61.  https://doi.org/10.1038/nature05725.CrossRefPubMedGoogle Scholar
  46. 46.
    Tanaka Y, et al. Early ontogenic origin of the hematopoietic stem cell lineage. Proc Natl Acad Sci U S A. 2012;109:4515–20.  https://doi.org/10.1073/pnas.1115828109.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Tanaka Y, et al. Circulation-independent differentiation pathway from extraembryonic mesoderm toward hematopoietic stem cells via hemogenic angioblasts. Cell Rep. 2014;8:31–9.  https://doi.org/10.1016/j.celrep.2014.05.055.CrossRefPubMedGoogle Scholar
  48. 48.
    Eliades A, et al. The hemogenic competence of endothelial progenitors is restricted by Runx1 silencing during embryonic development. Cell Rep. 2016;15:2185–99.  https://doi.org/10.1016/j.celrep.2016.05.001.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Jaffredo T, Gautier R, Eichmann A, Dieterlen-Lievre F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development. 1998;125:4575–83.PubMedGoogle Scholar
  50. 50.
    Ciau-Uitz A, Walmsley M, Patient R. Distinct origins of adult and embryonic blood in Xenopus. Cell. 2000;102:787–96.CrossRefGoogle Scholar
  51. 51.
    Dieterlen-Lievre F, Martin C. Diffuse intraembryonic hemopoiesis in normal and chimeric avian development. Dev Biol. 1981;88:180–91.CrossRefGoogle Scholar
  52. 52.
    Garcia-Porrero JA, Godin IE, Dieterlen-Lievre F. Potential intraembryonic hemogenic sites at pre-liver stages in the mouse. Anat Embryol (Berl). 1995;192:425–35.CrossRefGoogle Scholar
  53. 53.
    Pardanaud L, Yassine F, Dieterlen-Lievre F. Relationship between vasculogenesis, angiogenesis and haemopoiesis during avian ontogeny. Development. 1989;105:473–85.PubMedGoogle Scholar
  54. 54.
    Tavian M, et al. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood. 1996;87:67–72.PubMedGoogle Scholar
  55. 55.
    Wood HB, May G, Healy L, Enver T, Morriss-Kay GM. CD34 expression patterns during early mouse development are related to modes of blood vessel formation and reveal additional sites of hematopoiesis. Blood. 1997;90:2300–11.PubMedGoogle Scholar
  56. 56.
    Yoder MC, et al. Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity. 1997;7:335–44.CrossRefGoogle Scholar
  57. 57.
    Yoder MC, Hiatt K, Mukherjee P. In vivo repopulating hematopoietic stem cells are present in the murine yolk sac at day 9.0 postcoitus. Proc Natl Acad Sci U S A. 1997;94:6776–80.CrossRefGoogle Scholar
  58. 58.
    Taoudi S, et al. Extensive hematopoietic stem cell generation in the AGM region via maturation of VE-cadherin+CD45+ pre-definitive HSCs. Cell Stem Cell. 2008;3:99–108.  https://doi.org/10.1016/j.stem.2008.06.004.CrossRefPubMedGoogle Scholar
  59. 59.
    Rybtsov S, et al. Tracing the origin of the HSC hierarchy reveals an SCF-dependent, IL-3-independent CD43(−) embryonic precursor. Stem Cell Rep. 2014;3:489–501.  https://doi.org/10.1016/j.stemcr.2014.07.009.CrossRefGoogle Scholar
  60. 60.
    Rybtsov S, et al. Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region. J Exp Med. 2011;208:1305–15.  https://doi.org/10.1084/jem.20102419.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Dieterlen-Lievre F. On the origin of haemopoietic stem cells in the avian embryo: an experimental approach. J Embryol Exp Morphol. 1975;33:607–19.PubMedGoogle Scholar
  62. 62.
    Lux CT, et al. All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood. 2008;111:3435–8.  https://doi.org/10.1182/blood-2007-08-107086.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Gritz E, Hirschi KK. Specification and function of hemogenic endothelium during embryogenesis. Cell Mol Life Sci. 2016;73:1547–67.  https://doi.org/10.1007/s00018-016-2134-0.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Sturgeon CM, Ditadi A, Awong G, Kennedy M, Keller G. Wnt signaling controls the specification of definitive and primitive hematopoiesis from human pluripotent stem cells. Nat Biotechnol. 2014;32:554–61.  https://doi.org/10.1038/nbt.2915.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lacaud G, Kouskoff V. Hemangioblast, hemogenic endothelium, and primitive versus definitive hematopoiesis. Exp Hematol. 2017;49:19–24.  https://doi.org/10.1016/j.exphem.2016.12.009.CrossRefPubMedGoogle Scholar
  66. 66.
    Kennedy M, et al. T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures. Cell Rep. 2012;2:1722–35.  https://doi.org/10.1016/j.celrep.2012.11.003.CrossRefPubMedGoogle Scholar
  67. 67.
    Tian Y, et al. The first wave of T lymphopoiesis in zebrafish arises from aorta endothelium independent of hematopoietic stem cells. J Exp Med. 2017;214(11):3347.  https://doi.org/10.1084/jem.20170488.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Dzierzak E, Philipsen S. Erythropoiesis: development and differentiation. Cold Spring Harb Perspect Med. 2013;3:a011601.  https://doi.org/10.1101/cshperspect.a011601.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Zambidis ET, Peault B, Park TS, Bunz F, Civin CI. Hematopoietic differentiation of human embryonic stem cells progresses through sequential hematoendothelial, primitive, and definitive stages resembling human yolk sac development. Blood. 2005;106:860–70.  https://doi.org/10.1182/blood-2004-11-4522.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Murry CE, Keller G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell. 2008;132:661–80.  https://doi.org/10.1016/j.cell.2008.02.008.CrossRefPubMedGoogle Scholar
  71. 71.
    Kaufman DS, Hanson ET, Lewis RL, Auerbach R, Thomson JA. Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A. 2001;98:10716–21.  https://doi.org/10.1073/pnas.191362598.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Vodyanik MA, Bork JA, Thomson JA, Slukvin II. Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential. Blood. 2005;105:617–26.  https://doi.org/10.1182/blood-2004-04-1649.CrossRefPubMedGoogle Scholar
  73. 73.
    Vodyanik MA, Thomson JA, Slukvin II. Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures. Blood. 2006;108:2095–105.  https://doi.org/10.1182/blood-2006-02-003327.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Woll PS, et al. Wnt signaling promotes hematoendothelial cell development from human embryonic stem cells. Blood. 2008;111:122–31.  https://doi.org/10.1182/blood-2007-04-084186.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Ji J, et al. OP9 stroma augments survival of hematopoietic precursors and progenitors during hematopoietic differentiation from human embryonic stem cells. Stem Cells. 2008;26:2485–95.  https://doi.org/10.1634/stemcells.2008-0642.CrossRefPubMedGoogle Scholar
  76. 76.
    Ledran MH, et al. Efficient hematopoietic differentiation of human embryonic stem cells on stromal cells derived from hematopoietic niches. Cell Stem Cell. 2008;3:85–98.  https://doi.org/10.1016/j.stem.2008.06.001.CrossRefPubMedGoogle Scholar
  77. 77.
    Qiu C, Olivier EN, Velho M, Bouhassira EE. Globin switches in yolk sac-like primitive and fetal-like definitive red blood cells produced from human embryonic stem cells. Blood. 2008;111:2400–8.  https://doi.org/10.1182/blood-2007-07-102087.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Ochi K, et al. Multicolor staining of globin subtypes reveals impaired globin switching during erythropoiesis in human pluripotent stem cells. Stem Cells Transl Med. 2014;3:792–800.  https://doi.org/10.5966/sctm.2013-0216.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Chadwick K, et al. Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells. Blood. 2003;102:906–15.  https://doi.org/10.1182/blood-2003-03-0832.CrossRefPubMedGoogle Scholar
  80. 80.
    Ng ES, Davis RP, Azzola L, Stanley EG, Elefanty AG. Forced aggregation of defined numbers of human embryonic stem cells into embryoid bodies fosters robust, reproducible hematopoietic differentiation. Blood. 2005;106:1601–3.  https://doi.org/10.1182/blood-2005-03-0987.CrossRefPubMedGoogle Scholar
  81. 81.
    Kennedy M, D’Souza SL, Lynch-Kattman M, Schwantz S, Keller G. Development of the hemangioblast defines the onset of hematopoiesis in human ES cell differentiation cultures. Blood. 2007;109:2679–87.  https://doi.org/10.1182/blood-2006-09-047704.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Niwa A, et al. A novel serum-free monolayer culture for orderly hematopoietic differentiation of human pluripotent cells via mesodermal progenitors. PLoS One. 2011;6:e22261.  https://doi.org/10.1371/journal.pone.0022261.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Smith BW, et al. The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation. Blood. 2013;122:376–85.  https://doi.org/10.1182/blood-2012-11-466722.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Leung A, et al. Notch and aryl hydrocarbon receptor signaling impact definitive hematopoiesis from human pluripotent stem cells. Stem Cells. 2018;36(7):1004–1019.  https://doi.org/10.1002/stem.2822. Epub 2018 Apr 1.
  85. 85.
    Abazov VM, et al. Ratio of isolated photon cross sections in pp macro collisions at square root of s = 630 and 1800 GeV. Phys Rev Lett. 2001;87:251805.CrossRefGoogle Scholar
  86. 86.
    Davis RP, et al. Targeting a GFP reporter gene to the MIXL1 locus of human embryonic stem cells identifies human primitive streak-like cells and enables isolation of primitive hematopoietic precursors. Blood. 2008;111:1876–84.  https://doi.org/10.1182/blood-2007-06-093609.CrossRefPubMedGoogle Scholar
  87. 87.
    Pick M, Azzola L, Mossman A, Stanley EG, Elefanty AG. Differentiation of human embryonic stem cells in serum-free medium reveals distinct roles for bone morphogenetic protein 4, vascular endothelial growth factor, stem cell factor, and fibroblast growth factor 2 in hematopoiesis. Stem Cells. 2007;25:2206–14.  https://doi.org/10.1634/stemcells.2006-0713.CrossRefPubMedGoogle Scholar
  88. 88.
    Woll PS, Martin CH, Miller JS, Kaufman DS. Human embryonic stem cell-derived NK cells acquire functional receptors and cytolytic activity. J Immunol. 2005;175:5095–103.CrossRefGoogle Scholar
  89. 89.
    Jung HS, et al. A human VE-cadherin-tdTomato and CD43-green fluorescent protein dual reporter cell line for study endothelial to hematopoietic transition. Stem Cell Res. 2016;17:401–5.  https://doi.org/10.1016/j.scr.2016.09.004.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Wang Y, Nakayama N. WNT and BMP signaling are both required for hematopoietic cell development from human ES cells. Stem Cell Res. 2009;3:113–25.  https://doi.org/10.1016/j.scr.2009.06.001.CrossRefPubMedGoogle Scholar
  91. 91.
    Bunn HF. Erythropoietin. Cold Spring Harb Perspect Med. 2013;3:a011619.  https://doi.org/10.1101/cshperspect.a011619.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Radtke F, et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity. 1999;10:547–58.CrossRefGoogle Scholar
  93. 93.
    Allman D, Aster JC, Pear WS. Notch signaling in hematopoiesis and early lymphocyte development. Immunol Rev. 2002;187:75–86.CrossRefGoogle Scholar
  94. 94.
    Deutsch VR, Tomer A. Megakaryocyte development and platelet production. Br J Haematol. 2006;134:453–66.  https://doi.org/10.1111/j.1365-2141.2006.06215.x.CrossRefPubMedGoogle Scholar
  95. 95.
    Yoshihara H, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007;1:685–97.  https://doi.org/10.1016/j.stem.2007.10.020.CrossRefPubMedGoogle Scholar
  96. 96.
    Irion S, et al. Temporal specification of blood progenitors from mouse embryonic stem cells and induced pluripotent stem cells. Development. 2010;137:2829–39.  https://doi.org/10.1242/dev.042119.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Choi KD, et al. Identification of the hemogenic endothelial progenitor and its direct precursor in human pluripotent stem cell differentiation cultures. Cell Rep. 2012;2:553–67.  https://doi.org/10.1016/j.celrep.2012.08.002.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Zambidis ET, et al. Expression of angiotensin-converting enzyme (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells. Blood. 2008;112:3601–14.  https://doi.org/10.1182/blood-2008-03-144766.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Ng ES, et al. Differentiation of human embryonic stem cells to HOXA+ hemogenic vasculature that resembles the aorta-gonad-mesonephros. Nat Biotechnol. 2016;34:1168–79.  https://doi.org/10.1038/nbt.3702.CrossRefPubMedGoogle Scholar
  100. 100.
    Lu SJ, et al. Generation of functional hemangioblasts from human embryonic stem cells. Nat Methods. 2007;4:501–9.  https://doi.org/10.1038/nmeth1041.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Choi K. Hemangioblast development and regulation. Biochem Cell Biol. 1998;76:947–56.CrossRefGoogle Scholar
  102. 102.
    Fehling HJ, et al. Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation. Development. 2003;130:4217–27.CrossRefGoogle Scholar
  103. 103.
    Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature. 2004;432:625–30.  https://doi.org/10.1038/nature03122.CrossRefPubMedGoogle Scholar
  104. 104.
    North T, et al. Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development. 1999;126:2563–75.PubMedGoogle Scholar
  105. 105.
    Thambyrajah R, et al. New insights into the regulation by RUNX1 and GFI1(s) proteins of the endothelial to hematopoietic transition generating primordial hematopoietic cells. Cell Cycle. 2016;15:2108–14.  https://doi.org/10.1080/15384101.2016.1203491.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Ditadi A, et al. Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat Cell Biol. 2015;17:580–91.  https://doi.org/10.1038/ncb3161.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Notta F, et al. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011;333:218–21.  https://doi.org/10.1126/science.1201219.CrossRefPubMedGoogle Scholar
  108. 108.
    Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12:786–98.  https://doi.org/10.1038/nri3311.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Ito M, et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002;100:3175–82.  https://doi.org/10.1182/blood-2001-12-0207.CrossRefPubMedGoogle Scholar
  110. 110.
    McDermott SP, Eppert K, Lechman ER, Doedens M, Dick JE. Comparison of human cord blood engraftment between immunocompromised mouse strains. Blood. 2010;116:193–200.  https://doi.org/10.1182/blood-2010-02-271841.CrossRefPubMedGoogle Scholar
  111. 111.
    Lu M, Kardel MD, O’Connor MD, Eaves CJ. Enhanced generation of hematopoietic cells from human hepatocarcinoma cell-stimulated human embryonic and induced pluripotent stem cells. Exp Hematol. 2009;37:924–36.  https://doi.org/10.1016/j.exphem.2009.05.007.CrossRefPubMedGoogle Scholar
  112. 112.
    Wang L, et al. Generation of hematopoietic repopulating cells from human embryonic stem cells independent of ectopic HOXB4 expression. J Exp Med. 2005;201:1603–14.  https://doi.org/10.1084/jem.20041888.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Suzuki N, et al. Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation. Mol Ther. 2013;21:1424–31.  https://doi.org/10.1038/mt.2013.71.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Amabile G, et al. In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells. Blood. 2013;121:1255–64.  https://doi.org/10.1182/blood-2012-06-434407.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Hentze H, et al. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res. 2009;2:198–210.  https://doi.org/10.1016/j.scr.2009.02.002.CrossRefPubMedGoogle Scholar
  116. 116.
    Tsukada M, et al. In Vivo Generation of Engraftable Murine Hematopoietic Stem Cells by Gfi1b, c-Fos, and Gata2 Overexpression within Teratoma. Stem Cell Rep. 2017;9:1024–33.  https://doi.org/10.1016/j.stemcr.2017.08.010.CrossRefGoogle Scholar
  117. 117.
    Yamanaka S, Takahashi K. Induction of pluripotent stem cells from mouse fibroblast cultures. Tanpakushitsu Kakusan Koso. 2006;51:2346–51.PubMedGoogle Scholar
  118. 118.
    Kyba M, Perlingeiro RC, Daley GQ. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell. 2002;109:29–37.CrossRefGoogle Scholar
  119. 119.
    Elcheva I, et al. Direct induction of haematoendothelial programs in human pluripotent stem cells by transcriptional regulators. Nat Commun. 2014;5:4372.  https://doi.org/10.1038/ncomms5372.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Pereira CF, et al. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell. 2013;13:205–18.  https://doi.org/10.1016/j.stem.2013.05.024.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Batta K, Florkowska M, Kouskoff V, Lacaud G. Direct reprogramming of murine fibroblasts to hematopoietic progenitor cells. Cell Rep. 2014;9:1871–84.  https://doi.org/10.1016/j.celrep.2014.11.002.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Doulatov S, et al. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell. 2013;13:459–70.  https://doi.org/10.1016/j.stem.2013.09.002.CrossRefPubMedGoogle Scholar
  123. 123.
    Riddell J, et al. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell. 2014;157:549–64.  https://doi.org/10.1016/j.cell.2014.04.006.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Sandler VM, et al. Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Nature. 2014;511:312–8.  https://doi.org/10.1038/nature13547.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Lis R, et al. Conversion of adult endothelium to immunocompetent haematopoietic stem cells. Nature. 2017;545:439–45.  https://doi.org/10.1038/nature22326.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Sugimura R, et al. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature. 2017;545:432–8.  https://doi.org/10.1038/nature22370.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol. 2005;33:259–71.  https://doi.org/10.1016/j.exphem.2004.11.007.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Bauer DE, Kamran SC, Orkin SH. Reawakening fetal hemoglobin: prospects for new therapies for the beta-globin disorders. Blood. 2012;120:2945–53.  https://doi.org/10.1182/blood-2012-06-292078.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Sankaran VG, Xu J, Orkin SH. Advances in the understanding of haemoglobin switching. Br J Haematol. 2010;149:181–94.  https://doi.org/10.1111/j.1365-2141.2010.08105.x.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Peschle C, et al. Haemoglobin switching in human embryos: asynchrony of zeta----alpha and epsilon----gamma-globin switches in primitive and definite erythropoietic lineage. Nature. 1985;313:235–8.CrossRefGoogle Scholar
  131. 131.
    Yang CT, et al. Human induced pluripotent stem cell derived erythroblasts can undergo definitive erythropoiesis and co-express gamma and beta globins. Br J Haematol. 2014;166:435–48.  https://doi.org/10.1111/bjh.12910.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Patterson M, et al. Defining the nature of human pluripotent stem cell progeny. Cell Res. 2012;22:178–93.  https://doi.org/10.1038/cr.2011.133.CrossRefPubMedGoogle Scholar
  133. 133.
    Vanuytsel K, et al. Induced pluripotent stem cell-based mapping of β -globin expression throughout human erythropoietic development. Blood Adv. 2018;2(15):1998–2011.  https://doi.org/10.1182/bloodadvances.2018020560
  134. 134.
    Kelley JM, Daley GQ. Hematopoietic defects and iPSC disease modeling: lessons learned. Immunol Lett. 2013;155:18–20.  https://doi.org/10.1016/j.imlet.2013.09.018.CrossRefPubMedGoogle Scholar
  135. 135.
    Ceccaldi R, et al. Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell. 2012;11:36–49.  https://doi.org/10.1016/j.stem.2012.05.013.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Tulpule A, et al. Knockdown of Fanconi anemia genes in human embryonic stem cells reveals early developmental defects in the hematopoietic lineage. Blood. 2010;115:3453–62.  https://doi.org/10.1182/blood-2009-10-246694.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Tanno T, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096–101.  https://doi.org/10.1038/nm1629.CrossRefPubMedGoogle Scholar
  138. 138.
    Tanno T, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114:181–6.  https://doi.org/10.1182/blood-2008-12-195503.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Kautz L, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46:678–84.  https://doi.org/10.1038/ng.2996.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Agarwal S, et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature. 2010;464:292–6.  https://doi.org/10.1038/nature08792.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Muller LU, et al. Overcoming reprogramming resistance of Fanconi anemia cells. Blood. 2012;119:5449–57.  https://doi.org/10.1182/blood-2012-02-408674.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Tulpule A, et al. Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction. Cell Stem Cell. 2013;12:727–36.  https://doi.org/10.1016/j.stem.2013.04.002.CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Cherry AB, et al. Induced pluripotent stem cells with a mitochondrial DNA deletion. Stem Cells. 2013;31:1287–97.  https://doi.org/10.1002/stem.1354.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Garcon L, et al. Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients. Blood. 2013;122:912–21.  https://doi.org/10.1182/blood-2013-01-478321.CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Zou J, Mali P, Huang X, Dowey SN, Cheng L. Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease. Blood. 2011;118:4599–608.  https://doi.org/10.1182/blood-2011-02-335554.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Park S, et al. A Comprehensive, ethnically diverse library of sickle cell disease-specific induced pluripotent stem cells. Stem Cell Rep. 2017;8:1076–85.  https://doi.org/10.1016/j.stemcr.2016.12.017.CrossRefGoogle Scholar
  147. 147.
    Li C, et al. Novel HDAd/EBV reprogramming vector and highly efficient Ad/CRISPR-cas sickle cell disease gene correction. Sci Rep. 2016;6:30422.  https://doi.org/10.1038/srep30422.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Xie F, et al. Seamless gene correction of beta-thalassemia mutations in patient-specific iPSCs using CRISPR/Cas9 and piggyBac. Genome Res. 2014;24:1526–33.  https://doi.org/10.1101/gr.173427.114.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Ou Z, et al. The combination of CRISPR/Cas9 and iPSC technologies in the gene therapy of human beta-thalassemia in mice. Sci Rep. 2016;6:32463.  https://doi.org/10.1038/srep32463.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Niu X, et al. Combining single strand oligodeoxynucleotides and CRISPR/Cas9 to correct gene mutations in beta-thalassemia-induced pluripotent stem cells. J Biol Chem. 2016;291:16576–85.  https://doi.org/10.1074/jbc.M116.719237.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Phanthong P, et al. Enhancement of beta-globin gene expression in thalassemic IVS2-654 induced pluripotent stem cell-derived erythroid cells by modified U7 snRNA. Stem Cells Transl Med. 2017;6:1059–69.  https://doi.org/10.1002/sctm.16-0121.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Kumano K, et al. Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples. Blood. 2012;119:6234–42.  https://doi.org/10.1182/blood-2011-07-367441.CrossRefPubMedGoogle Scholar
  153. 153.
    Fok WC, et al. p53 mediates failure of human definitive hematopoiesis in dyskeratosis congenita. Stem Cell Rep. 2017;9:409–18.  https://doi.org/10.1016/j.stemcr.2017.06.015.CrossRefGoogle Scholar
  154. 154.
    Raya A, et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature. 2009;460:53–9.  https://doi.org/10.1038/nature08129.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Chlon TM, et al. Overcoming pluripotent stem cell dependence on the repair of endogenous DNA damage. Stem Cell Rep. 2016;6:44–54.  https://doi.org/10.1016/j.stemcr.2015.12.001.CrossRefGoogle Scholar
  156. 156.
    Yung SK, et al. Brief report: human pluripotent stem cell models of fanconi anemia deficiency reveal an important role for fanconi anemia proteins in cellular reprogramming and survival of hematopoietic progenitors. Stem Cells. 2013;31:1022–9.  https://doi.org/10.1002/stem.1308.CrossRefPubMedGoogle Scholar
  157. 157.
    Vanuytsel K, et al. FANCA knockout in human embryonic stem cells causes a severe growth disadvantage. Stem Cell Res. 2014;13:240–50.  https://doi.org/10.1016/j.scr.2014.07.005.CrossRefPubMedGoogle Scholar
  158. 158.
    Liu GH, et al. Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs. Nat Commun. 2014;5:4330.  https://doi.org/10.1038/ncomms5330.CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med. 2013;3:a011643.  https://doi.org/10.1101/cshperspect.a011643.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Steinberg MH, Ohene-Frempong K, Heeney MM. In: Forget BG, Steinberg MH, Higgs DR, Weatherall DJ, editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management Ch. 19. Cambridge: Cambridge University Press; 2009. p. 437–496.Google Scholar
  161. 161.
    Chang KH, et al. Definitive-like erythroid cells derived from human embryonic stem cells coexpress high levels of embryonic and fetal globins with little or no adult globin. Blood. 2006;108:1515–23.  https://doi.org/10.1182/blood-2005-11-011874.CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Platt OS, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330:1639–44.  https://doi.org/10.1056/NEJM199406093302303.CrossRefPubMedGoogle Scholar
  163. 163.
    Platt OS, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325:11–6.  https://doi.org/10.1056/NEJM199107043250103.CrossRefPubMedGoogle Scholar
  164. 164.
    Piel FB, Steinberg MH, Rees DC. Sickle Cell Disease. N Engl J Med. 2017;377:305.  https://doi.org/10.1056/NEJMc1706325.CrossRefPubMedGoogle Scholar
  165. 165.
    Stamatoyannopoulos G, Navas PA, Li Q. In: Forget BG, Steinberg MH, Higgs DR, Weatherall DJ, editors. Disorders of hemoglobin: genetics, pathophysiology, and clinical management Ch. 5. Cambridge: Cambridge University Press; 2009. p. 86–100.Google Scholar
  166. 166.
    Rahmig S, et al. Improved human erythropoiesis and platelet formation in humanized NSGW41 mice. Stem Cell Rep. 2016;7:591–601.  https://doi.org/10.1016/j.stemcr.2016.08.005.CrossRefGoogle Scholar
  167. 167.
    Chen B, et al. Complement depletion improves human red blood cell reconstitution in immunodeficient mice. Stem Cell Rep. 2017;9:1034–42.  https://doi.org/10.1016/j.stemcr.2017.08.018.CrossRefGoogle Scholar
  168. 168.
    Fiorini C, et al. Developmentally-faithful and effective human erythropoiesis in immunodeficient and Kit mutant mice. Am J Hematol. 2017;92:E513–9.  https://doi.org/10.1002/ajh.24805.CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Hu Z, Van Rooijen N, Yang YG. Macrophages prevent human red blood cell reconstitution in immunodeficient mice. Blood. 2011;118:5938–46.  https://doi.org/10.1182/blood-2010-11-321414.CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    McIntosh BE, et al. Nonirradiated NOD,B6.SCID Il2rgamma−/− Kit(W41/W41) (NBSGW) mice support multilineage engraftment of human hematopoietic cells. Stem Cell Rep. 2015;4:171–80.  https://doi.org/10.1016/j.stemcr.2014.12.005.CrossRefGoogle Scholar
  171. 171.
    Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014;123:481–5.  https://doi.org/10.1182/blood-2013-09-528067.CrossRefPubMedGoogle Scholar
  172. 172.
    Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3:711–5.  https://doi.org/10.1038/nrd1470.CrossRefPubMedGoogle Scholar
  173. 173.
    Lian Q, Chow Y, Esteban MA, Pei D, Tse HF. Future perspective of induced pluripotent stem cells for diagnosis, drug screening and treatment of human diseases. Thromb Haemost. 2010;104:39–44.  https://doi.org/10.1160/TH10-05-0269.CrossRefPubMedGoogle Scholar
  174. 174.
    Deshmukh RS, Kovacs KA, Dinnyes A. Drug discovery models and toxicity testing using embryonic and induced pluripotent stem-cell-derived cardiac and neuronal cells. Stem Cells Int. 2012;2012:379569.  https://doi.org/10.1155/2012/379569.CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Chun YS, Byun K, Lee B. Induced pluripotent stem cells and personalized medicine: current progress and future perspectives. Anat Cell Biol. 2011;44:245–55.  https://doi.org/10.5115/acb.2011.44.4.245.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Kim Vanuytsel
    • 1
    • 2
  • Martin H. Steinberg
    • 1
    • 2
  • George J. Murphy
    • 1
    • 2
    Email author
  1. 1.Section of Hematology and Oncology, Department of MedicineBoston University School of MedicineBostonUSA
  2. 2.Center for Regenerative Medicine (CReM)Boston University and Boston Medical CenterBostonUSA

Personalised recommendations