title: Differentiation of human embryonic stem cells to HOXA+hemogenic vasculature that resembles the aorta-gonad-mesonephros.
abstract: The ability to generate hematopoietic stem cells from human pluripotent cells would enable many biomedical applications. We find that hematopoietic CD34+cells in spin embryoid bodies derived from human embryonic stem cells (hESCs) lack HOXA expression compared with repopulation-competent human cord blood CD34+cells, indicating incorrect mesoderm patterning. Using reporter hESC lines to track the endothelial (SOX17) to hematopoietic (RUNX1C) transition that occurs in development, we show that simultaneous modulation of WNT and ACTIVIN signaling yields CD34+hematopoietic cells with HOXA expression that more closely resembles that of cord blood. The cultures generate a network of aorta-like SOX17+vessels from which RUNX1C+blood cells emerge, similar to hematopoiesis in the aorta-gonad-mesonephros (AGM). Nascent CD34+hematopoietic cells and corresponding cells sorted from human AGM show similar expression of cell surface receptors, signaling molecules and transcription factors. Our findings provide an approach to mimic in vitro a key early stage in human hematopoiesis for the generation of AGM-derived hematopoietic lineages from hESCs.
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.|Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ng
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Azzola
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.|Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Freya F
authors.initials: FF
authors.lastname: Bruveris
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, USA.|Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calvanese
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Phipson
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Katerina
authors.initials: K
authors.lastname: Vlahos
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Hirst
authors.affiliation: Department of Anatomy and Neuroscience, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Vanta J
authors.initials: VJ
authors.lastname: Jokubaitis
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Shanghai, P.R. China.
authors.forename: Qing C
authors.initials: QC
authors.lastname: Yu
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Jovana
authors.initials: J
authors.lastname: Maksimovic
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Liebscher
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Vania
authors.initials: V
authors.lastname: Januar
authors.affiliation: Commonwealth Scientific and Industrial Research Organisation (CSIRO), Manufacturing, Clayton, Victoria, Australia.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.|Commonwealth Scientific and Industrial Research Organisation (CSIRO), Manufacturing, Clayton, Victoria, Australia.
authors.forename: Brenda
authors.initials: B
authors.lastname: Williams
authors.affiliation: Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Aude
authors.initials: A
authors.lastname: Conscience
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Durnall
authors.affiliation: Wisconsin Institutes for Discovery, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Jackson
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research Precinct, Melbourne, Victoria, Australia.
authors.forename: Magdaline
authors.initials: M
authors.lastname: Costa
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Elliott
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.|Commonwealth Scientific and Industrial Research Organisation (CSIRO), Manufacturing, Clayton, Victoria, Australia.
authors.forename: David N
authors.initials: DN
authors.lastname: Haylock
authors.affiliation: Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.|Commonwealth Scientific and Industrial Research Organisation (CSIRO), Manufacturing, Clayton, Victoria, Australia.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Nilsson
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Richard
authors.identifier: http://orcid.org/0000-0002-9510-4181
authors.initials: R
authors.lastname: Saffery
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany.|Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB), Stuttgart, Germany.|Department of Medicine/Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Katja
authors.initials: K
authors.lastname: Schenke-Layland
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Alicia
authors.identifier: http://orcid.org/0000-0001-9788-5690
authors.initials: A
authors.lastname: Oshlack
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, USA.|Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, California, USA.|Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Hanna K A
authors.initials: HK
authors.lastname: Mikkola
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.|Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.|Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Edouard G
authors.initials: EG
authors.lastname: Stanley
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.|Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.|Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Elefanty
mesh_terms: D001011:Aorta / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology; D006066:Gonads / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008650:Mesonephros / Q000166:cytology* / Q000196:embryology* / Q000254:growth & development; D018919:Neovascularization, Physiologic / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; C088144:HoxA protein