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NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells

Author

Listed:
  • Gene I. Uenishi

    (University of Wisconsin
    University of Wisconsin School of Medicine and Public Health)

  • Ho Sun Jung

    (University of Wisconsin)

  • Akhilesh Kumar

    (University of Wisconsin)

  • Mi Ae Park

    (University of Wisconsin)

  • Brandon K. Hadland

    (University of Washington School of Medicine
    Fred Hutchinson Cancer Research Center)

  • Ethan McLeod

    (University of Wisconsin)

  • Matthew Raymond

    (University of Wisconsin
    University of Wisconsin School of Veterinary Medicine)

  • Oleg Moskvin

    (University of Wisconsin)

  • Catherine E. Zimmerman

    (University of Wisconsin)

  • Derek J. Theisen

    (University of Wisconsin)

  • Scott Swanson

    (Morgridge Institute for Research)

  • Owen Tamplin

    (University of Illinois)

  • Leonard I. Zon

    (Harvard Medical School and Howard Hughes Medical Institute)

  • James A. Thomson

    (Morgridge Institute for Research
    University of Wisconsin School of Medicine and Public Health
    University of California)

  • Irwin D. Bernstein

    (University of Washington School of Medicine
    Fred Hutchinson Cancer Research Center)

  • Igor I. Slukvin

    (University of Wisconsin
    University of Wisconsin School of Medicine and Public Health
    University of Wisconsin School of Medicine and Public Health)

Abstract

NOTCH signaling is required for the arterial specification and formation of hematopoietic stem cells (HSCs) and lympho-myeloid progenitors in the embryonic aorta-gonad-mesonephros region and extraembryonic vasculature from a distinct lineage of vascular endothelial cells with hemogenic potential. However, the role of NOTCH signaling in hemogenic endothelium (HE) specification from human pluripotent stem cell (hPSC) has not been studied. Here, using a chemically defined hPSC differentiation system combined with the use of DLL1-Fc and DAPT to manipulate NOTCH, we discover that NOTCH activation in hPSC-derived immature HE progenitors leads to formation of CD144+CD43−CD73−DLL4+Runx1 + 23-GFP+ arterial-type HE, which requires NOTCH signaling to undergo endothelial-to-hematopoietic transition and produce definitive lympho-myeloid and erythroid cells. These findings demonstrate that NOTCH-mediated arterialization of HE is an essential prerequisite for establishing definitive lympho-myeloid program and suggest that exploring molecular pathways that lead to arterial specification may aid in vitro approaches to enhance definitive hematopoiesis from hPSCs.

Suggested Citation

  • Gene I. Uenishi & Ho Sun Jung & Akhilesh Kumar & Mi Ae Park & Brandon K. Hadland & Ethan McLeod & Matthew Raymond & Oleg Moskvin & Catherine E. Zimmerman & Derek J. Theisen & Scott Swanson & Owen Tamp, 2018. "NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04134-7
    DOI: 10.1038/s41467-018-04134-7
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    Cited by:

    1. Shicheng Sun & Ali Motazedian & Jacky Y. Li & Kevin Wijanarko & Joe Jiang Zhu & Kothila Tharmarajah & Kathleen A. Strumila & Anton Shkaruta & L. Rayburn Nigos & Jacqueline V. Schiesser & Yi Yu & Paul , 2024. "Efficient generation of human NOTCH ligand-expressing haemogenic endothelial cells as infrastructure for in vitro haematopoiesis and lymphopoiesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. B. Edginton-White & A. Maytum & S. G. Kellaway & D. K. Goode & P. Keane & I. Pagnuco & S. A. Assi & L. Ames & M. Clarke & P. N. Cockerill & B. Göttgens & J. B. Cazier & C. Bonifer, 2023. "A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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