title: HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo.
abstract: Hypoxia affects many physiologic processes during early stages of mammalian ontogeny, particularly placental and vascular development. In the adult, the hypoxic bone marrow microenvironment plays a role in regulating hematopoietic stem cell (HSC) function. HSCs are generated from the major vasculature of the embryo, but whether the hypoxic response affects the generation of these HSCs is as yet unknown. Here we examined whether Hypoxia Inducible Factor1-alpha (HIF1α), a key modulator of the response to hypoxia, is essential for HSC development. We found hypoxic cells in embryonic tissues that generate and expand hematopoietic cells (aorta, placenta and fetal liver), and specifically aortic endothelial and hematopoietic cluster cells. A Cre/loxP conditional knockout (cKO) approach was taken to delete HIF1α in Vascular Endothelial-Cadherin expressing endothelial cells, the precursors to definitive hematopoietic cells. Functional assays show that HSC and hematopoietic progenitor cells (HPCs) are significantly reduced in cKO aorta and placenta. Moreover, decreases in phenotypic aortic hematopoietic cluster cells in cKO embryos indicate that HIF1α is necessary for generation and/or expansion of HPCs and HSCs. cKO adult BM HSCs are also affected under transplantation conditions. Thus, HIF1α is a regulator of HSC generation and function beginning at the earliest embryonic stages.
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Parisa
authors.initials: P
authors.lastname: Imanirad
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Parham
authors.initials: P
authors.lastname: Solaimani Kartalaei
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Crisan
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: Vink
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada-Inagawa
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Emma
authors.initials: E
authors.lastname: de Pater
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kurek
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Polynikis
authors.initials: P
authors.lastname: Kaimakis
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Reiner
authors.initials: R
authors.lastname: van der Linden
authors.affiliation: Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Speck
authors.affiliation: Erasmus MC Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: e.dzierzak@erasmusmc.nl.
authors.forename: Elaine
authors.initials: E
authors.lastname: Dzierzak
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D015820:Cadherins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D002469:Cell Separation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000166:cytology; D011247:Pregnancy; D014184:Transplantation, Homologous
chemical_list: D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit