title: Transforming Growth Factor β Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells.
abstract: Hematopoietic stem cells (HSCs) are self-renewing multipotent stem cells that generate mature blood lineages throughout life. They, together with hematopoietic progenitor cells (collectively known as HSPCs), emerge from hemogenic endothelium in the floor of the embryonic dorsal aorta by an endothelial-to-hematopoietic transition (EHT). Here we demonstrate that transforming growth factor β (TGFβ) is required for HSPC specification and that it regulates the expression of the Notch ligand Jagged1a in endothelial cells prior to EHT, in a striking parallel with the epithelial-to-mesenchymal transition (EMT). The requirement for TGFβ is two fold and sequential: autocrine via Tgfβ1a and Tgfβ1b produced in the endothelial cells themselves, followed by a paracrine input of Tgfβ3 from the notochord, suggesting that the former programs the hemogenic endothelium and the latter drives EHT. Our findings have important implications for the generation of HSPCs from pluripotent cells in vitro.
authors: Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; BHF Centre of Research Excellence, Oxford, UK. Electronic address: rui.monteiro@imm.ox.ac.uk.
authors: Rui
authors: R
authors: Monteiro
authors: Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors: Philip
authors: P
authors: Pinheiro
authors: Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors: Nicola
authors: N
authors: Joseph
authors: Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors: Tessa
authors: T
authors: Peterkin
authors: Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors: Jana
authors: J
authors: Koth
authors: Computational Biology Research Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors: Emmanouela
authors: E
authors: Repapi
authors: Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors: Florian
authors: F
authors: Bonkhofer
authors: Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
authors: Arif
authors: A
authors: Kirmizitas
authors: Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; BHF Centre of Research Excellence, Oxford, UK. Electronic address: roger.patient@imm.ox.ac.uk.
authors: Roger
authors: R
authors: Patient
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004730:Endothelium, Vascular / Q000196:embryology*; D058750:Epithelial-Mesenchymal Transition; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D000072100:Jagged-1 Protein / Q000096:biosynthesis / Q000235:genetics; D060172:Morpholinos / Q000235:genetics; D039902:Multipotent Stem Cells / Q000166:cytology; D009672:Notochord / Q000196:embryology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism*; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D000072100:Jagged-1 Protein; D060172:Morpholinos; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins; C000606276:jag1a protein, zebrafish; C472526:runx1 protein, zebrafish
keywords: EHT; TGFβ; hematopoietic stem cell; jag1a; notch; zebrafish