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

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 J Tamplin, Leonard I Zon, James A Thomson, Irwin D Bernstein, Igor I Slukvin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1828
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - May 2018
Externally publishedYes

Keywords

  • Animals
  • Antigens, CD/immunology
  • Arteries/cytology
  • Calcium-Binding Proteins
  • Cell Differentiation
  • Cell Line
  • Cell Lineage
  • Cell Tracking/instrumentation
  • Coculture Techniques
  • Embryo, Mammalian/cytology
  • Endothelium, Vascular/cytology
  • Erythroid Precursor Cells/cytology
  • Hemangioblasts/cytology
  • Hematopoiesis
  • Hematopoietic Stem Cells/metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Lymphoid Progenitor Cells/cytology
  • Membrane Proteins/metabolism
  • Mice
  • Myeloid Progenitor Cells/cytology
  • Neovascularization, Physiologic
  • Pluripotent Stem Cells/cytology
  • Receptors, Notch/metabolism
  • Signal Transduction

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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