title: Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells.
abstract: Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and small interfering RNA to Notch receptors we have demonstrated that Notch1, but not Notch2, activation induced hairy and enhancer of split 1 (HES1) expression and generation of committed hematopoietic progenitors. Using gain- and loss-of-function approaches, this was shown to be attributed to Notch-signaling regulation through HES1, which dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs endothelial fate specification.
authors.affiliation: McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Jung Bok
authors.initials: JB
authors.lastname: Lee
authors.forename: Tamra E
authors.initials: TE
authors.lastname: Werbowetski-Ogilvie
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Brendan A S
authors.initials: BA
authors.lastname: McIntyre
authors.forename: Angelique
authors.initials: A
authors.lastname: Schnerch
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Hong
authors.forename: In-Hyun
authors.initials: IH
authors.lastname: Park
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Mickie
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D018398:Homeodomain Proteins; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C497761:NOTCH1 protein, human; C078493:HES1 protein, human