title: The Notch ligand DLL4 specifically marks human hematoendothelial progenitors and regulates their hematopoietic fate.
abstract: Notch signaling is essential for definitive hematopoiesis, but its role in human embryonic hematopoiesis is largely unknown. We show that in hESCs the expression of the Notch ligand DLL4 is induced during hematopoietic differentiation. We found that DLL4 is only expressed in a sub-population of bipotent hematoendothelial progenitors (HEPs) and segregates their hematopoietic versus endothelial potential. We demonstrate at the clonal level and through transcriptome analyses that DLL4(high) HEPs are enriched in endothelial potential, whereas DLL4(low/-) HEPs are committed to the hematopoietic lineage, albeit both populations still contain bipotent cells. Moreover, DLL4 stimulation enhances hematopoietic differentiation of HEPs and increases the amount of clonogenic hematopoietic progenitors. Confocal microscopy analysis of whole differentiating embryoid bodies revealed that DLL4(high) HEPs are located close to DLL4(low/-) HEPs, and at the base of clusters of CD45+ cells, resembling intra-aortic hematopoietic clusters found in mouse embryos. We propose a model for human embryonic hematopoiesis in which DLL4(low/-) cells within hemogenic endothelium receive Notch-activating signals from DLL4(high) cells, resulting in an endothelial-to-hematopoietic transition and their differentiation into CD45+ hematopoietic cells.
authors.affiliation: Gene Regulation, Stem Cells & Development Laboratory, GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Ayllón
authors.affiliation: Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Bueno
authors.affiliation: Gene Regulation, Stem Cells & Development Laboratory, GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Ramos-Mejía
authors.affiliation: Gene Regulation, Stem Cells & Development Laboratory, GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Navarro-Montero
authors.affiliation: Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Prieto
authors.affiliation: Gene Regulation, Stem Cells & Development Laboratory, GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
authors.forename: P J
authors.initials: PJ
authors.lastname: Real
authors.affiliation: Gene Regulation, Stem Cells & Development Laboratory, GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Romero
authors.affiliation: Centro de Biologia Molecular Severo Ochoa (CBM-SO), CSIC-UAM, Campus de la Universidad Autonoma de Madrid, Madrid, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: García-León
authors.affiliation: Centro de Biologia Molecular Severo Ochoa (CBM-SO), CSIC-UAM, Campus de la Universidad Autonoma de Madrid, Madrid, Spain.
authors.forename: M L
authors.initials: ML
authors.lastname: Toribio
authors.affiliation: Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Bigas
authors.affiliation: 1] Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Barcelona, Spain [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Menendez
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D058732:Embryoid Bodies; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004727:Endothelium / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C064045:delta protein