Haematopoietic stem and progenitor cells from human pluripotent stem cells.
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.
- PMID: 28514439
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.
2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
3 Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
4 Manton Center for Orphan Disease Research, Boston, Massachusetts 02115, USA.
5 Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA.
6 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
7 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02215, USA.
8 Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
9 Department of Biology, Brandeis University, Waltham, Massachusetts 02453, USA.
10 Program in Computer Science, Harvard University, Cambridge, Massachusetts, USA.
11 McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada.
12 Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.
13 Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.