NOTCH Signaling Specifies Arterial-type Definitive Hemogenic Endothelium from Human Pluripotent Stem Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2018 May 10

PMID 29739946

Citations 80

Authors

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

Affiliations

Soon will be listed here.

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 CD144CD43CD73DLL4Runx1 + 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.

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