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Nature
05 25, 2017;545 (7655): 432-438.

Haematopoietic stem and progenitor cells from human pluripotent stem cells.

Ryohichi Sugimura, Deepak Kumar Jha, Areum Han, Clara Soria-Valles, Edroaldo Lummertz da Rocha, Yi-Fen Lu, Jeremy A Goettel, Erik Serrao, R Grant Rowe, Mohan Malleshaiah, Irene Wong, Patricia Sousa, Ted N Zhu, Andrea Ditadi, Gordon Keller, Alan N Engelman, Scott B Snapper, Sergei Doulatov, George Q Daley
Author Information
  1. Ryohichi Sugimura: 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.
  2. Deepak Kumar Jha: 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.
  3. Areum Han: 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.
  4. Clara Soria-Valles: 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.
  5. Edroaldo Lummertz da Rocha: 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.
  6. Yi-Fen Lu: 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.
  7. Jeremy A Goettel: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
  8. Erik Serrao: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02215, USA.
  9. R Grant Rowe: 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.
  10. Mohan Malleshaiah: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
  11. Irene Wong: Department of Biology, Brandeis University, Waltham, Massachusetts 02453, USA.
  12. Patricia Sousa: 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.
  13. Ted N Zhu: Program in Computer Science, Harvard University, Cambridge, Massachusetts, USA.
  14. Andrea Ditadi: McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada.
  15. Gordon Keller: McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada.
  16. Alan N Engelman: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02215, USA.
  17. Scott B Snapper: Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA.
  18. Sergei Doulatov: 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.
  19. George Q Daley: 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.
PMID: 28514439 DOI: 10.1038/nature22370

Abstract

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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Grants

  1. U01 HL134812/NHLBI NIH HHS
  2. R37 AI039394/NIAID NIH HHS
  3. K01 DK106311/NIDDK NIH HHS
  4. /Howard Hughes Medical Institute
  5. DK034854/NIDDK NIH HHS
  6. U01 HL100001/NHLBI NIH HHS
  7. P30 DK034854/NIDDK NIH HHS
  8. R24 DK092760/NIDDK NIH HHS
  9. R00 HL123484/NHLBI NIH HHS

MeSH Term

Animals
Cell Differentiation
Cell Lineage
Cellular Reprogramming
Core Binding Factor Alpha 2 Subunit
Endothelium
Female
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Homeobox A10 Proteins
Homeodomain Proteins
Humans
Mice
Pluripotent Stem Cells
Proto-Oncogene Proteins
Repressor Proteins
Trans-Activators
Transcription Factors
Transcriptional Regulator ERG

Chemicals

Core Binding Factor Alpha 2 Subunit
ERG protein, human
HOXA5 protein, human
Homeobox A10 Proteins
Homeodomain Proteins
LCOR protein, human
Proto-Oncogene Proteins
RUNX1 protein, human
Repressor Proteins
Trans-Activators
Transcription Factors
Transcriptional Regulator ERG
homeobox protein HOXA9
proto-oncogene protein Spi-1
HOXA10 protein, human
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000105 (inDrop single cell RNA-seq of hematopoietic cells derived from human pluripotent stem cells)

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