Lineage-tracing hematopoietic stem cell origins in vivo to efficiently and rapidly reconstruct human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells.
Authors/Creators
- Fowler, Jonas L.1, 2, 3
- Zheng, Sherry Li1, 2
- Nguyen, Alana1, 2, 4
- Chen, Angela1, 2, 5
- Xiong, Xiaochen1, 2, 6
- Chai, Timothy1, 2
- Chen, Julie Y.1, 2
- Karigane, Daiki1, 7
- Banuelos, Allison M.1, 8
- Niizuma, Kouta1, 9
- Kayamori, Kensuke1, 7
- Nishimura, Toshinobu1, 9, 10
- Cromer, M. Kyle11
- Gonzalez-Perez, David12
- Mason, Charlotte12
- Liu, Daniel Dan1, 8
- Yilmaz, Leyla1, 8
- Miquerol, Lucile13
- Porteus, Matthew H.1, 14
- Luca, Vincent C.12
- Majeti, Ravindra1, 7
- Nakauchi, Hiromitsu1, 9
- Red-Horse, Kristy1, 15
- Weissman, Irving L.1, 8
- Ang, Lay Teng (Contact person)1
- Loh, Kyle M. (Contact person)1, 2
- 1. Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
- 2. Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA
- 3. Present address: Walking Fish Therapeutics, South San Francisco, CA 94080, USA
- 4. Present address: School of Veterinary Medicine, University of California, Davis, Davis, CA 95616, USA
- 5. Present address: Orca Bio, Menlo Park, CA 94025, USA
- 6. Present address: Department of Biology, Stanford University, Stanford, CA 94305, USA
- 7. Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA
- 8. Department of Pathology, Stanford University, Stanford, CA 94305, USA
- 9. Department of Genetics, Stanford University, Stanford, CA 94305, USA
- 10. Present address: Century Therapeutics, Philadelphia, PA 19104, USA
- 11. Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
- 12. Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA
- 13. Aix-Marseille Universite´ , CNRS UMR 7288, IBDM, Marseille 13288, France
- 14. Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
- 15. Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
Description
The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.5 days (E8.5–E11) but subsequently cease, delimiting a narrow time frame for HSC formation in vivo. Guided by the arterial origins of blood, we efficiently and rapidly differentiate human pluripotent stem cells (hPSCs) into posterior primitive streak, lateral mesoderm, artery endothelium, hemogenic endothelium, and >90% pure hematopoietic progenitors within 10 days. hPSC-derived hematopoietic progenitors generate T, B, NK, erythroid, and myeloid cells in vitro and, critically, express hallmark HSC transcription factors HLF and HOXA5-HOXA10, which were previously challenging to upregulate.We differentiated hPSCs into highly enriched HLF+ HOXA+ hematopoietic progenitors with near-stoichiometric efficiency by blocking formation of unwanted lineages at each differentiation step. hPSC-derived HLF+ HOXA+ hematopoietic progenitors could avail both basic research and cellular therapies.
Files
23 Fowler et al Developmental Cell.pdf
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Additional details
Dates
- Accepted
-
2024-03-01