Uenishi GI, Jung HS, Kumar A, Park MA, Hadland BK, McLeod E, Raymond M, Moskvin O, Zimmerman CE, Theisen DJ, Swanson S, J Tamplin O, Zon LI, Thomson JA, Bernstein ID, Slukvin II. NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells. Nat Commun. 2018 05 08; 9(1):1828.

Citation

Uenishi GI, Jung HS, Kumar A, Park MA, Hadland BK, McLeod E, Raymond M, Moskvin O, Zimmerman CE, Theisen DJ, Swanson S, J Tamplin O, Zon LI, Thomson JA, Bernstein ID, Slukvin II. 2018. NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells. Nature communications. 9(1):1828. Pubmed: 29739946 DOI:10.1038/s41467-018-04134-7

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.

Related Faculty

Leonard Zon, M.D.

Zon Lab

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.