Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Progress towards generation of human haematopoietic stem cells

Nature Cell Biology volume 18, pages 1111–1117 (2016)Cite this article

Subjects

Abstract

De novo generation of haematopoietic stem cells from different human pluripotent stem cell sources remains a high priority for haematology and regenerative medicine. At present, efficient derivation of functional haematopoietic stem cells with the capability for definitive in vivo engraftment and multi-lineage potential remains challenging. Here, we discuss recent progress and strategies to overcome obstacles that have thwarted past efforts. In addition, we review promising advances in the generation of mature blood lineages and the potential of induced pluripotent stem cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The haematopoietic hierarchy.
Figure 2: Defining features of haematopoietic stem cells (HSCs).

Similar content being viewed by others

References

  1. Orkin, S. H. & Zon, L. I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132, 631–644 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gragert, L. et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. New Engl. J. Med. 371, 339–348 (2014).

    CAS  PubMed  Google Scholar 

  3. Walasek, M. A., van Os, R. & de Haan, G. Hematopoietic stem cell expansion: challenges and opportunities. Ann. NY Acad. Sci. 1266, 138–150 (2012).

    CAS  PubMed  Google Scholar 

  4. Fares, I. et al. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 345, 1509–1512 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Gao, Y. et al. Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells. Nat. Commun. 6, 6328 (2015).

    CAS  PubMed  Google Scholar 

  6. Qu, Q. et al. Endothelial progenitor cells promote efficient ex vivo expansion of cord blood-derived hematopoietic stem/progenitor cells. Cytotherapy 18, 452–464 (2016).

    CAS  PubMed  Google Scholar 

  7. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    CAS  PubMed  Google Scholar 

  8. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  9. Park, I. H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).

    CAS  PubMed  Google Scholar 

  10. Slukvin, I. I. Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells. Blood 122, 4035–4046 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Vo, L. T. & Daley, G. Q. De novo generation of HSCs from somatic and pluripotent stem cell sources. Blood 125, 2641–2648 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ebina, W. & Rossi, D. J. Transcription factor-mediated reprogramming toward hematopoietic stem cells. EMBO J. 34, 694–709 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Daniel, M. G., Pereira, C. F., Lemischka, I. R. & Moore, K. A. Making a hematopoietic stem cell. Trends Cell Biol. 26, 202–214 (2016).

    PubMed  Google Scholar 

  14. Amabile, G. et al. In vivo generation of transplantable human hematopoietic cells from induced pluripotent stem cells. Blood 121, 1255–1264 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Suzuki, N. et al. Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation. Mol. Ther. 21, 1424–1431 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ema, H. et al. Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice. Dev. Cell 8, 907–914 (2005).

    CAS  PubMed  Google Scholar 

  17. Murry, C. E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).

    CAS  PubMed  Google Scholar 

  18. Kardel, M. D. & Eaves, C. J. Modeling human hematopoietic cell development from pluripotent stem cells. Exp. Hematol. 40, 601–611 (2012).

    CAS  PubMed  Google Scholar 

  19. Sauvageau, G. et al. Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells. Proc. Natl Acad. Sci. USA 91, 12223–12227 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kyba, M., Perlingeiro, R. C. & Daley, G. Q. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109, 29–37 (2002).

    CAS  PubMed  Google Scholar 

  21. Wang, L. et al. Generation of hematopoietic repopulating cells from human embryonic stem cells independent of ectopic HOXB4 expression. J. Exp. Med. 201, 1603–1614 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ledran, M. H. et al. Efficient hematopoietic differentiation of human embryonic stem cells on stromal cells derived from hematopoietic niches. Cell Stem Cell 3, 85–98 (2008).

    CAS  PubMed  Google Scholar 

  23. Pick, M., Azzola, L., Mossman, A., Stanley, E. G. & Elefanty, A. G. 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 25, 2206–2214 (2007).

    CAS  PubMed  Google Scholar 

  24. Chadwick, K. et al. Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells. Blood 102, 906–915 (2003).

    CAS  PubMed  Google Scholar 

  25. Keller, G., Kennedy, M., Papayannopoulou, T. & Wiles, M. V. Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol. Cell. Biol. 13, 473–486 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Matsuoka, S. et al. Generation of definitive hematopoietic stem cells from murine early yolk sac and paraaortic splanchnopleures by aorta–gonad–mesonephros region-derived stromal cells. Blood 98, 6–12 (2001).

    CAS  PubMed  Google Scholar 

  27. Clarke, R. L., Robitaille, A. M., Moon, R. T. & Keller, G. A. Quantitative proteomic analysis of hemogenic endothelium reveals differential regulation of hematopoiesis by SOX17. Stem Cell Rep. 5, 291–304 (2015).

    CAS  Google Scholar 

  28. Kennedy, M. et al. T lymphocyte potential marks the emergence of definitive hematopoietic progenitors in human pluripotent stem cell differentiation cultures. Cell Rep. 2, 1722–1735 (2012).

    CAS  PubMed  Google Scholar 

  29. Sturgeon, C. M., 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. 32, 554–561 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Medvinsky, A. & Dzierzak, E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906 (1996).

    CAS  PubMed  Google Scholar 

  31. Boisset, J. C. et al. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464, 116–120 (2010).

    CAS  PubMed  Google Scholar 

  32. Eilken, H. M., Nishikawa, S. & Schroeder, T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457, 896–900 (2009).

    CAS  PubMed  Google Scholar 

  33. Ditadi, A. et al. Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat. Cell Biol. 17, 580–591 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Souilhol, C. et al. Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells. Nat. Commun. 7, 10784 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Choi, K. D., Vodyanik, M. A. & Slukvin, I. I. Generation of mature human myelomonocytic cells through expansion and differentiation of pluripotent stem cell-derived lin−CD34+CD43+CD45+ progenitors. J. Clin. Invest. 119, 2818–2829 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Davis, R. L., Weintraub, H. & Lassar, A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).

    CAS  PubMed  Google Scholar 

  37. Morris, S. A. et al. Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell 158, 889–902 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sandler, V. M., Lailler, N. & Bouhassira, E. E. Reprogramming of embryonic human fibroblasts into fetal hematopoietic progenitors by fusion with human fetal liver CD34+ cells. PLoS ONE 6, e18265 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Szabo, E. et al. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468, 521–526 (2010).

    CAS  PubMed  Google Scholar 

  40. Mitchell, R. et al. Molecular evidence for OCT4-induced plasticity in adult human fibroblasts required for direct cell fate conversion to lineage specific progenitors. Stem Cells 32, 2178–2187 (2014).

    CAS  PubMed  Google Scholar 

  41. Pulecio, J. et al. Conversion of human fibroblasts into monocyte-like progenitor cells. Stem Cells 32, 2923–2938 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Pereira, C. F. et al. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell 13, 205–218 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Batta, K., Florkowska, M., Kouskoff, V. & Lacaud, G. Direct reprogramming of murine fibroblasts to hematopoietic progenitor cells. Cell Rep. 9, 1871–1884 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Elcheva, I. et al. Direct induction of haematoendothelial programs in human pluripotent stem cells by transcriptional regulators. Nat. Commun. 5, 4372 (2014).

    CAS  PubMed  Google Scholar 

  45. Sandler, V. M. et al. Reprogramming human endothelial cells to haematopoietic cells requires vascular induction. Nature 511, 312–318 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Riddell, J. et al. Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157, 549–564 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Doulatov, S. et al. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell 13, 459–470 (2013).

    CAS  PubMed  Google Scholar 

  48. Kaufman, D. S. Toward clinical therapies using hematopoietic cells derived from human pluripotent stem cells. Blood 114, 3513–3523 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Olivier, E. N., Qiu, C., Velho, M., Hirsch, R. E. & Bouhassira, E. E. Large-scale production of embryonic red blood cells from human embryonic stem cells. Exp. Hematol. 34, 1635–1642 (2006).

    CAS  PubMed  Google Scholar 

  50. Giarratana, M. C. et al. Proof of principle for transfusion of in vitro-generated red blood cells. Blood 118, 5071–5079 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Migliaccio, A. R., Whitsett, C., Papayannopoulou, T. & Sadelain, M. The potential of stem cells as an in vitro source of red blood cells for transfusion. Cell Stem Cell 10, 115–119 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee, H. Y. et al. PPAR-α and glucocorticoid receptor synergize to promote erythroid progenitor self-renewal. Nature 522, 474–477 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Rousseau, G. F., Giarratana, M. C. & Douay, L. Large-scale production of red blood cells from stem cells: what are the technical challenges ahead? Biotechnol. J. 9, 28–38 (2014).

    CAS  PubMed  Google Scholar 

  54. Chang, C. J. et al. Production of embryonic and fetal-like red blood cells from human induced pluripotent stem cells. PLoS ONE 6, e25761 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Giani, F. C. et al. Targeted application of human genetic variation can improve red blood cell production from stem cells. Cell Stem Cell 18, 73–78 (2016).

    CAS  PubMed  Google Scholar 

  56. Shi, J. et al. Engineered red blood cells as carriers for systemic delivery of a wide array of functional probes. Proc. Natl Acad. Sci. USA 111, 10131–10136 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Takayama, N. et al. Generation of functional platelets from human embryonic stem cells in vitro via ES–sacs, VEGF-promoted structures that concentrate hematopoietic progenitors. Blood 111, 5298–5306 (2008).

    CAS  PubMed  Google Scholar 

  58. Lu, S. J. et al. Platelets generated from human embryonic stem cells are functional in vitro and in the microcirculation of living mice. Cell Res. 21, 530–545 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Nakamura, S. et al. Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells. Cell Stem Cell 14, 535–548 (2014).

    CAS  PubMed  Google Scholar 

  60. Liu, Y. et al. Efficient generation of megakaryocytes from human induced pluripotent stem cells using food and drug administration-approved pharmacological reagents. Stem Cells Transl. Med. 4, 309–319 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang, N. et al. CRISPR/Cas9-mediated conversion of human platelet alloantigen allotypes. Blood 127, 675–680 (2015).

    PubMed  Google Scholar 

  62. Lachmann, N. et al. Large-scale hematopoietic differentiation of human induced pluripotent stem cells provides granulocytes or macrophages for cell replacement therapies. Stem Cell Rep. 4, 282–296 (2015).

    CAS  Google Scholar 

  63. Timmermans, F. et al. Generation of T cells from human embryonic stem cell-derived hematopoietic zones. J. Immunol. 182, 6879–6888 (2009).

    CAS  PubMed  Google Scholar 

  64. Themeli, M., Riviere, I. & Sadelain, M. New cell sources for T cell engineering and adoptive immunotherapy. Cell Stem Cell 16, 357–366 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Smith, M. J. et al. In vitro T-cell generation from adult, embryonic, and induced pluripotent stem cells: many roads to one destination. Stem Cells 33, 3174–3180 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Themeli, M. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928–933 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Agarwal, S. et al. Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients. Nature 464, 292–296 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Park, I. H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Hanna, J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318, 1920–1923 (2007).

    CAS  PubMed  Google Scholar 

  70. Jeong, M. et al. Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat. Genet. 46, 17–23 (2014).

    CAS  PubMed  Google Scholar 

  71. Alvarez-Dominguez, J. R., Hu, W., Gromatzky, A. A. & Lodish, H. F. Long noncoding RNAs during normal and malignant hematopoiesis. Int. J. Hematol. 99, 531–541 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. O'Connell, R. M. Endogenous miR-29a regulates HSC function in mammals. Blood 125, 2180–2181 (2015).

    CAS  PubMed  Google Scholar 

  73. Roy, L. et al. MiR-24 is required for hematopoietic differentiation of mouse embryonic stem cells. PLoS Genet. 11, e1004959 (2015).

    PubMed  PubMed Central  Google Scholar 

  74. Copley, M. R. et al. The Lin28b–let-7–Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nat. Cell Biol. 15, 916–925 (2013).

    CAS  PubMed  Google Scholar 

  75. Nimmo, R. et al. MiR-142-3p controls the specification of definitive hemangioblasts during ontogeny. Dev. Cell 26, 237–249 (2013).

    CAS  PubMed  Google Scholar 

  76. Adamo, L. et al. Biomechanical forces promote embryonic haematopoiesis. Nature 459, 1131–1135 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. North, T. E. et al. Hematopoietic stem cell development is dependent on blood flow. Cell 137, 736–748 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Lee, H. J., Li, N., Evans, S. M., Diaz, M. F. & Wenzel, P. L. Biomechanical force in blood development: extrinsic physical cues drive pro-hematopoietic signaling. Differentiation 86, 92–103 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim, P. G. et al. Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence. J. Exp. Med. 212, 633–648 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Diaz, M. F. et al. Biomechanical forces promote blood development through prostaglandin E2 and the cAMP–PKA signaling axis. J. Exp. Med. 212, 665–680 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Torisawa, Y. S. et al. Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nat. Methods 11, 663–669 (2014).

    CAS  PubMed  Google Scholar 

  82. Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Cahan, P. et al. CellNet: network biology applied to stem cell engineering. Cell 158, 903–915 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Gori, J. L. et al. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells. J. Clin. Invest. 125, 1243–1254 (2015).

    PubMed  PubMed Central  Google Scholar 

  85. Kobari, L. et al. Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model. Haematologica 97, 1795–1803 (2012).

    PubMed  PubMed Central  Google Scholar 

  86. Dias, J. et al. Generation of red blood cells from human induced pluripotent stem cells. Stem Cells Dev. 20, 1639–1647 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Choi, K. D., Vodyanik, M. & Slukvin, I. I. Hematopoietic differentiation and production of mature myeloid cells from human pluripotent stem cells. Nat. Protoc. 6, 296–313 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

L.W. is supported by the Young Investigator Award Program at Heidelberg University. The authors thank D. Ebrahimi-Fakhari, A. Saffari, M. Cesana, S. Doulatov, R. Sugimura and L. Vo for helpful discussions.

Author information

Authors and Affiliations

  1. Division of Pediatric Hematology/Oncology, USA; in the Department of Biological Chemistry and Molecular Pharmacology, Lara Wahlster and George Q. Daley are at the Stem Cell Transplantation Program, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Children's Hospital Boston and Dana Farber Cancer Institute, Boston, 02115 Massachusetts, Harvard Medical School, Boston, 02115 Massachusetts, USA; and at the Harvard Stem Cell Institute, Boston, 02115 Massachusetts, USA,

    Lara Wahlster & George Q. Daley

  2. in the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Lara Wahlster & George Q. Daley

  3. L.W. is also in the Department of General Pediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, 69120, Germany

    Lara Wahlster

Authors
  1. Lara Wahlster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George Q. Daley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George Q. Daley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wahlster, L., Daley, G. Progress towards generation of human haematopoietic stem cells. Nat Cell Biol 18, 1111–1117 (2016). https://doi.org/10.1038/ncb3419

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb3419

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing