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+CD43CD73DLL4+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.

Details

Title
NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells
Author
Uenishi, Gene I 1 ; Ho Sun Jung 2 ; Kumar, Akhilesh 2   VIAFID ORCID Logo  ; Park, Mi Ae 2   VIAFID ORCID Logo  ; Hadland, Brandon K 3 ; McLeod, Ethan 2 ; Raymond, Matthew 4 ; Moskvin, Oleg 2   VIAFID ORCID Logo  ; Zimmerman, Catherine E 2 ; Theisen, Derek J 2   VIAFID ORCID Logo  ; Swanson, Scott 5   VIAFID ORCID Logo  ; Tamplin, Owen J 6   VIAFID ORCID Logo  ; Zon, Leonard I 7   VIAFID ORCID Logo  ; Thomson, James A 8 ; Bernstein, Irwin D 3 ; Slukvin, Igor I 9   VIAFID ORCID Logo 

 Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 
 Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA 
 Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 
 Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA; Department of Biomedical Sciences, University of Wisconsin School of Veterinary Medicine, Madison, WI, USA 
 Morgridge Institute for Research, Madison, WI, USA 
 Department of Pharmacology, University of Illinois, Chicago, IL, USA 
 Stem Cell Program and Division of Hematology/Oncology, Children’s Hospital Boston, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA 
 Morgridge Institute for Research, Madison, WI, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA 
 Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA 
Pages
1-14
Publication year
2018
Publication date
May 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2036168103
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.