Long-term engrafting multilineage hematopoietic cells differentiated from human induced pluripotent stem cells
Hematopoietic stem cells (HSCs) derived from human induced pluripotent stem cells (iPS cells) have important biomedical applications. We identified differentiation conditions that generate HSCs defined by robust long-term multilineage engraftment in immune-deficient NOD,B6.Prkdc<sup>scid</sup> Il2rg<sup>tm1Wjl/SzJ</sup> Kit<sup>W41/W41</sup> mice. We guided differentiating iPS cells, as embryoid bodies in a defined culture medium supplemented with retinyl acetate, through HOXA-patterned mesoderm to hemogenic endothelium specified by bone morphogenetic protein 4 and vascular endothelial growth factor (VEGF). Removal of VEGF facilitated an efficient endothelial-to-hematopoietic transition, evidenced by release into the culture medium of CD34<sup>+</sup> blood cells, which were cryopreserved. Intravenous transplantation of two million thawed CD34<sup>+</sup> cells differentiated from four independent iPS cell lines produced multilineage bone marrow engraftment in 25-50% of immune-deficient recipient mice. These functionally defined, multipotent CD34<sup>+</sup> hematopoietic cells, designated iPS cell-derived HSCs (iHSCs), produced levels of engraftment similar to those achieved following umbilical cord blood transplantation. Our study provides a step toward the goal of generating HSCs for clinical translation.
Authors
- Hasindu S. Edirisinghe (ORCID: https://orcid.org/0009-0008-2139-6952)
- Feiyang Ma (ORCID: https://orcid.org/0000-0002-6260-0787)
- Mirana Ramialison (ORCID: https://orcid.org/0000-0001-6315-4777)
- Ali Motazedian (ORCID: https://orcid.org/0000-0003-2424-1119)
- Hieu T. Nim (ORCID: https://orcid.org/0000-0001-9320-0236)
- Alexander Maytum (ORCID: https://orcid.org/0009-0003-2341-7239)
- Ritika Saxena (ORCID: https://orcid.org/0000-0001-5412-2255)
- Vincenzo Calvanese (ORCID: https://orcid.org/0000-0002-7937-1511)
- Shicheng Sun (ORCID: https://orcid.org/0000-0002-9584-9909)
- Edouard G. Stanley (ORCID: https://orcid.org/0000-0002-6389-3665)
- Tanya Labonne
- Hanna Mikkola (ORCID: https://orcid.org/0000-0002-3400-1496)
- Nerida Sleebs
- Jacky Y. Li
- Gulcan Sarila
- Constanze Bonifer (ORCID: https://orcid.org/0000-0002-4267-0825)
- Andrew G. Elefanty (ORCID: https://orcid.org/0000-0001-6448-8314)
- Elizabeth Ng (ORCID: https://orcid.org/0000-0002-7970-8129)
- Freya Bruveris (ORCID: https://orcid.org/0000-0002-9365-1149)
- Sandra Capellera-Garcia (ORCID: https://orcid.org/0000-0002-5680-242X)
- Chantelle Inguanti
- Raymond Y. Yow
Institutions
- Royal Children's Hospital (AU)
- University of California, Los Angeles (US)
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Australian Regenerative Medicine Institute (AU)
- MRC Laboratory for Molecular Cell Biology (GB)
- Murdoch Children's Research Institute (AU)
- Broad Center (US)
- University College London (GB)
- Monash University (AU)
- University of Birmingham (GB)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2024-09-02
- DOI
- https://doi.org/10.1038/s41587-024-02360-7
- Citations
- 72
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 16.60
Funders
- Foundation for the National Institutes of Health
- California Institute for Regenerative Medicine
- Vetenskapsrådet
- Novo Nordisk Fonden
- Biotechnology and Biological Sciences Research Council
- National Health and Medical Research Council