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Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells. 2024
Jonas L Fowler, and
Sherry Li Zheng, and
Alana Nguyen, and
Angela Chen, and
Xiaochen Xiong, and
Timothy Chai, and
Julie Y Chen, and
Daiki Karigane, and
Allison M Banuelos, and
Kouta Niizuma, and
Kensuke Kayamori, and
Toshinobu Nishimura, and
M Kyle Cromer, and
David Gonzalez-Perez, and
Charlotte Mason, and
Daniel Dan Liu, and
Leyla Yilmaz, and
Lucile Miquerol, and
Matthew H Porteus, and
Vincent C Luca, and
Ravindra Majeti, and
Hiromitsu Nakauchi, and
Kristy Red-Horse, and
Irving L Weissman, and
Lay Teng Ang, and
Kyle M Loh
Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
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.
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