title: Distinct routes of lineage development reshape the human blood hierarchy across ontogeny.
abstract: In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a cell-sorting scheme to resolve myeloid (My), erythroid (Er), and megakaryocytic (Mk) fates from single CD34(+) cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with intermingled My, Er, and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead, only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult "two-tier" hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Faiyaz
authors.initials: F
authors.lastname: Notta
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sasan
authors.initials: S
authors.lastname: Zandi
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Naoya
authors.initials: N
authors.lastname: Takayama
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dobson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Olga I
authors.initials: OI
authors.lastname: Gan
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|Ontario Institute for Cancer Research, Toronto, Ontario Canada.
authors.forename: Gavin
authors.initials: G
authors.lastname: Wilson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kerstin B
authors.initials: KB
authors.lastname: Kaufmann
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: McLeod
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Elisa
authors.initials: E
authors.lastname: Laurenti
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, LMC, Station 12, Lausanne, CH-1015, Switzerland.
authors.forename: Cyrille F
authors.initials: CF
authors.lastname: Dunant
authors.affiliation: Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Ontario Institute for Cancer Research, Toronto, Ontario Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: McPherson
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|Ontario Institute for Cancer Research, Toronto, Ontario Canada.
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Stein
authors.affiliation: The Hospital for Sick Children Research Institute, University of Toronto, Ontario, Canada.
authors.forename: Yigal
authors.initials: Y
authors.lastname: Dror
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000166:cytology*; D005312:Fetal Blood / Q000166:cytology; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology*; D008533:Megakaryocytes / Q000166:cytology*; D039902:Multipotent Stem Cells / Q000166:cytology; D022423:Myeloid Cells / Q000166:cytology*; D014158:Transcription, Genetic
chemical_list: D018952:Antigens, CD34