1. NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells.
- Author
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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, and Slukvin II
- Subjects
- Animals, Antigens, CD immunology, Arteries metabolism, Calcium-Binding Proteins, Cell Differentiation, Cell Line, Cell Lineage, Cell Tracking instrumentation, Coculture Techniques, Embryo, Mammalian cytology, Endothelium, Vascular metabolism, Erythroid Precursor Cells cytology, Erythroid Precursor Cells immunology, Hemangioblasts immunology, Hematopoietic Stem Cells metabolism, Humans, Intercellular Signaling Peptides and Proteins metabolism, Lymphoid Progenitor Cells cytology, Lymphoid Progenitor Cells immunology, Membrane Proteins metabolism, Mice, Myeloid Progenitor Cells cytology, Myeloid Progenitor Cells immunology, Pluripotent Stem Cells immunology, Arteries cytology, Endothelium, Vascular cytology, Hemangioblasts cytology, Hematopoiesis, Neovascularization, Physiologic, Pluripotent Stem Cells cytology, Receptors, Notch metabolism, Signal Transduction
- 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.- Published
- 2018
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