Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells.
Jonas L Fowler, Sherry Li Zheng, Alana Nguyen, Angela Chen, Xiaochen Xiong, Timothy Chai, Julie Y Chen, Daiki Karigane, Allison M Banuelos, Kouta Niizuma, Kensuke Kayamori, Toshinobu Nishimura, M Kyle Cromer, David Gonzalez-Perez, Charlotte Mason, Daniel Dan Liu, Leyla Yilmaz, Lucile Miquerol, Matthew H Porteus, Vincent C Luca, Ravindra Majeti, Hiromitsu Nakauchi, Kristy Red-Horse, Irving L Weissman, Lay Teng Ang, Kyle M Loh
Author Information
Jonas L Fowler: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Sherry Li Zheng: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Alana Nguyen: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Angela Chen: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Xiaochen Xiong: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Timothy Chai: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Julie Y Chen: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
Daiki Karigane: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Allison M Banuelos: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Kouta Niizuma: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Kensuke Kayamori: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Toshinobu Nishimura: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
M Kyle Cromer: Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
David Gonzalez-Perez: Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.
Charlotte Mason: Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.
Daniel Dan Liu: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Leyla Yilmaz: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Lucile Miquerol: Aix-Marseille Universit��, CNRS UMR 7288, IBDM, Marseille 13288, France.
Matthew H Porteus: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
Vincent C Luca: Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL 33612, USA.
Ravindra Majeti: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Hiromitsu Nakauchi: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Kristy Red-Horse: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Irving L Weissman: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Lay Teng Ang: Institute for Stem Cell Biology & Regenerative Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: layteng@stanford.edu.
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. Electronic address: kyleloh@stanford.edu.
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.
