title: BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo.
abstract: Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment.
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands; BHF Centre for Cardiovascular Science, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Crisan
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands; Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Parham
authors.initials: P
authors.lastname: Solaimani Kartalaei
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Neagu
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands.
authors.forename: Sofia
authors.initials: S
authors.lastname: Karkanpouna
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada-Inagawa
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands.
authors.forename: Caterina
authors.initials: C
authors.lastname: Purini
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands; Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Vink
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands.
authors.forename: Reinier
authors.initials: R
authors.lastname: van der Linden
authors.affiliation: Center for Biomics, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands.
authors.forename: Wilfred
authors.initials: W
authors.lastname: van Ijcken
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Susana M
authors.initials: SM
authors.lastname: Chuva de Sousa Lopes
authors.affiliation: Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Rui
authors.initials: R
authors.lastname: Monteiro
authors.affiliation: Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
authors.forename: Christine
authors.initials: C
authors.lastname: Mummery
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, Erasmus MC Stem Cell Institute, 3000 CA Rotterdam, the Netherlands; Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Electronic address: elaine.dzierzak@ed.ac.uk.
authors.forename: Elaine
authors.initials: E
authors.lastname: Dzierzak
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D053823:Hedgehog Proteins; D051785:Smad Proteins; D042461:Vascular Endothelial Growth Factor A
keywords: AGM; BMP; HPSCs; Hh; VEGF; development; hematopoiesis; hematopoietic stem/progenitor cells