PUBLICATION

Transforming Growth Factor ? Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells

Authors
Monteiro, R., Pinheiro, P., Joseph, N., Peterkin, T., Koth, J., Repapi, E., Bonkhofer, F., Kirmizitas, A., Patient, R.
ID
ZDB-PUB-160809-6
Date
2016
Source
Developmental Cell   38(4): 358-70 (Journal)
Registered Authors
Koth, Jana, Monteiro, Rui, Patient, Roger K., Peterkin, Tessa, Pinheiro, Philip
Keywords
EHT, TGF?, hematopoietic stem cell, jag1a, notch, zebrafish
MeSH Terms
  • Zebrafish/embryology*
  • Transforming Growth Factor beta3/genetics
  • Transforming Growth Factor beta3/metabolism*
  • Animals, Genetically Modified
  • Core Binding Factor Alpha 2 Subunit/genetics
  • Endothelium, Vascular/embryology*
  • Animals
  • Transforming Growth Factor beta1/genetics
  • Transforming Growth Factor beta1/metabolism*
  • Morpholinos/genetics
  • Zebrafish Proteins/biosynthesis
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Jagged-1 Protein/biosynthesis
  • Jagged-1 Protein/genetics
  • Cell Differentiation
  • Vascular Endothelial Growth Factor A/metabolism
  • Hematopoietic Stem Cells/cytology*
  • Notochord/embryology
  • Signal Transduction
  • Transforming Growth Factor beta2/genetics
  • Transforming Growth Factor beta2/metabolism*
  • Multipotent Stem Cells/cytology
  • Epithelial-Mesenchymal Transition
(all 24)
PubMed
27499523 Full text @ Dev. Cell
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.
Genes / Markers
Figures
Figure Gallery (10 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WTchemical treatment: EC 3.4.23.46 (memapsin 2) inhibitorPrim-5
WTchemical treatment: EC 3.4.23.46 (memapsin 2) inhibitorPrim-5
WTchemical treatment: vascular endothelial growth factor receptor antagonist26+ somites
WTchemical treatment: vascular endothelial growth factor receptor antagonist26+ somites
WTchemical treatment: vascular endothelial growth factor receptor antagonist26+ somites
WTchemical treatment: vascular endothelial growth factor receptor antagonist26+ somites
WTchemical treatment: vascular endothelial growth factor receptor antagonistPrim-5
WTchemical treatment: vascular endothelial growth factor receptor antagonistPrim-5
WT + MO1-tgfbr2bstandard conditionsPrim-5
WT + MO1-tgfbr2bstandard conditionsPrim-5
1 - 10 of 44
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
la2TgTransgenic Insertion
    s843TgTransgenic Insertion
      s896TgTransgenic Insertion
        y1TgTransgenic Insertion
          zf169TgTransgenic Insertion
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            bmp4MO3-bmp4MRPHLNO
            jag1aMO2-jag1aMRPHLNO
            kdrlMO2-kdrlMRPHLNO
            runx1MO1-runx1MRPHLNO
            tgfb1aMO5-tgfb1aMRPHLNO
            tgfb1aMO6-tgfb1aMRPHLNO
            tgfb1bMO1-tgfb1bMRPHLNO
            tgfb1bMO2-tgfb1bMRPHLNO
            tgfb2MO2-tgfb2MRPHLNO
            tgfb2MO3-tgfb2MRPHLNO
            1 - 10 of 14
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            Fish
            Antibodies
            Name Type Antigen Genes Isotypes Host Organism
            Ab1-tgfbr2monoclonal
              IgG2aMouse
              1 - 1 of 1
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              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              EGFPEFGEGFP
              mCherryEFGmCherry
              1 - 2 of 2
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              Mapping
              No data available