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 Tamplin, Leonard I. Zon, James A. Thomson, Irwin D. Bernstein and Igor I. Slukvin ()
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Gene I. Uenishi: University of Wisconsin
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
Ethan McLeod: University of Wisconsin
Matthew Raymond: University of Wisconsin
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
Irwin D. Bernstein: University of Washington School of Medicine
Igor I. Slukvin: University of Wisconsin

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04134-7

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