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

Rui Monteiro; Philip Pinheiro; Nicola Joseph; Tessa Peterkin; Jana Koth; Emmanouela Repapi; Florian Bonkhofer; Arif Kirmizitas; Roger Patient

doi:10.1016/j.devcel.2016.06.024

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

Dev Cell. 2016 Aug 22;38(4):358-70. doi: 10.1016/j.devcel.2016.06.024. Epub 2016 Aug 4.

Authors

Rui Monteiro¹, Philip Pinheiro², Nicola Joseph², Tessa Peterkin², Jana Koth², Emmanouela Repapi³, Florian Bonkhofer², Arif Kirmizitas², Roger Patient⁴

Affiliations

¹ 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.
² Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
³ Computational Biology Research Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
⁴ 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.

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.

Keywords: EHT; TGFβ; hematopoietic stem cell; jag1a; notch; zebrafish.

MeSH terms

Animals
Animals, Genetically Modified
Cell Differentiation
Core Binding Factor Alpha 2 Subunit / genetics
Endothelium, Vascular / embryology*
Epithelial-Mesenchymal Transition
Hematopoietic Stem Cells / cytology*
Jagged-1 Protein / biosynthesis
Jagged-1 Protein / genetics
Morpholinos / genetics
Multipotent Stem Cells / cytology
Notochord / embryology
Signal Transduction
Transforming Growth Factor beta1 / genetics
Transforming Growth Factor beta1 / metabolism*
Transforming Growth Factor beta2 / genetics
Transforming Growth Factor beta2 / metabolism*
Transforming Growth Factor beta3 / genetics
Transforming Growth Factor beta3 / metabolism*
Vascular Endothelial Growth Factor A / metabolism
Zebrafish / embryology*
Zebrafish Proteins / biosynthesis
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism

Substances

Core Binding Factor Alpha 2 Subunit
Jagged-1 Protein
Morpholinos
Transforming Growth Factor beta1
Transforming Growth Factor beta2
Transforming Growth Factor beta3
Vascular Endothelial Growth Factor A
Vegfaa protein, zebrafish
Zebrafish Proteins
jag1a protein, zebrafish
runx1 protein, zebrafish

Abstract

MeSH terms

Substances

Grants and funding