A variety of tissue lineages can be differentiated from pluripotent stem cells by mimicking embryonic development through stepwise exposure to morphogens, or by conversion of one differentiated cell type into another by enforced expression of master transcription factors. Here, to yield functional human haematopoietic stem cells, we perform morphogen-directed differentiation of human pluripotent stem cells into haemogenic endothelium followed by screening of 26 candidate haematopoietic stem-cell-specifying transcription factors for their capacity to promote multi-lineage haematopoietic engraftment in mouse hosts. We recover seven transcription factors (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1 and SPI1) that are sufficient to convert haemogenic endothelium into haematopoietic stem and progenitor cells that engraft myeloid, B and T cells in primary and secondary mouse recipients. Our combined approach of morphogen-driven differentiation and transcription-factor-mediated cell fate conversion produces haematopoietic stem and progenitor cells from pluripotent stem cells and holds promise for modelling haematopoietic disease in humanized mice and for therapeutic strategies in genetic blood disorders.

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We thank T. Schlaeger and the Boston Children’s Hospital Human ESC Core Facility, R. Mathieu from the flow cytometry core, R. Renee, A. Ratner, and S. Boswell from Harvard Medical School for RNA-seq, the orchestra team at Harvard Medical School for providing high-performance computing, D. Kaufman for providing the RUNX1c+24 hPSC line, N. Gerry for microarray and SNP array analysis, and T. North, C. Brendel and J. Powers for reading the manuscript. This work was supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases (R24DK092760), the National Institute of Allergy and Infectious Diseases (R37AI039394), and the National Heart, Lung, Blood Institute Progenitor Cell Biology Consortium (UO1-HL100001) and the Progenitor Cell Translation Consortium (UO1-HL134812); Alex’s Lemonade Stand Foundation; and the Doris Duke Medical Foundation. G.Q.D. is an associate member of the Broad Institute and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. R.S. is supported by an American Society of Hematology Scholar Fellowship. C.S.V. is an EMBO (ALTF 1240-2015) fellow. S.D. is supported by the K99/R00HL123484. J.A.G. is supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK106311) and the Crohn’s and Colitis Foundation of America CDA 352644 (J.A.G.), S.B.S. is supported by NIDDK (DK034854), the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research.

Author information

Author notes

    • Sergei Doulatov

    Present address: Department of Medicine, Division of Hematology, University of Washington, Seattle, Washington 98195, USA.

    • Deepak Kumar Jha
    •  & Areum Han

    These authors contributed equally to this work.


  1. Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute, Boston Children’s Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Ryohichi Sugimura
    • , Deepak Kumar Jha
    • , Areum Han
    • , Clara Soria-Valles
    • , Edroaldo Lummertz da Rocha
    • , Yi-Fen Lu
    • , R. Grant Rowe
    • , Patricia Sousa
    • , Sergei Doulatov
    •  & George Q. Daley
  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Ryohichi Sugimura
    • , Deepak Kumar Jha
    • , Areum Han
    • , Clara Soria-Valles
    • , Edroaldo Lummertz da Rocha
    • , Yi-Fen Lu
    • , Patricia Sousa
    • , Sergei Doulatov
    •  & George Q. Daley
  3. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    • Ryohichi Sugimura
    • , Deepak Kumar Jha
    • , Clara Soria-Valles
    • , Edroaldo Lummertz da Rocha
    • , Yi-Fen Lu
    • , Patricia Sousa
    • , Sergei Doulatov
    •  & George Q. Daley
  4. Manton Center for Orphan Disease Research, Boston, Massachusetts 02115, USA

    • Ryohichi Sugimura
    • , Deepak Kumar Jha
    • , Clara Soria-Valles
    • , Edroaldo Lummertz da Rocha
    • , Yi-Fen Lu
    • , Patricia Sousa
    • , Sergei Doulatov
    •  & George Q. Daley
  5. Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA

    • Jeremy A. Goettel
    •  & Scott B. Snapper
  6. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    • Jeremy A. Goettel
    •  & Scott B. Snapper
  7. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02215, USA

    • Erik Serrao
    •  & Alan N. Engelman
  8. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

    • Mohan Malleshaiah
  9. Department of Biology, Brandeis University, Waltham, Massachusetts 02453, USA

    • Irene Wong
  10. Program in Computer Science, Harvard University, Cambridge, Massachusetts, USA

    • Ted N. Zhu
  11. McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada

    • Andrea Ditadi
    •  & Gordon Keller
  12. Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, USA

    • Scott B. Snapper
  13. Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA

    • George Q. Daley


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R.S. designed, performed, interpreted experiments, and wrote the paper. D.J., A.H., E.L.R., and T.N.Z. performed computational analysis of RNA-seq data. C.S.V., I.W., and P.S. assisted in iPSC culture, differentiation, and analyses of mice. C.S.V. replicated the entire process, independently. Y.L. performed globin expression analysis. R.R. performed cytospin of cells. M.M. performed flow cytometric analysis. D.J. contributed to writing and C.S.V. contributed to editing. E.S. and A.N.E. designed and interpreted integration sequencing experiments. J.A.G. and S.B.S. designed and interpreted TCRB rearrangement experiments. A.D. and G.K. instructed haemogenic endothelium induction. S.D. assisted in design and interpretation of experiments. G.Q.D. designed, interpreted experiments, and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to George Q. Daley.

Reviewer Information Nature thanks B. Gottgens and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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