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 J Tamplin; Leonard I Zon; James A Thomson; Irwin D Bernstein; Igor I Slukvin

doi:10.1038/s41467-018-04134-7

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 J Tamplin
, Leonard I Zon
, James A Thomson
, Irwin D Bernstein
, Igor I Slukvin

Research output: Contribution to journal › Article › peer-review

100 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1828
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04134-7
State	Published - May 2018
Externally published	Yes

Keywords

Animals
Antigens, CD/immunology
Arteries/cytology
Calcium-Binding Proteins
Cell Differentiation
Cell Line
Cell Lineage
Cell Tracking/instrumentation
Coculture Techniques
Embryo, Mammalian/cytology
Endothelium, Vascular/cytology
Erythroid Precursor Cells/cytology
Hemangioblasts/cytology
Hematopoiesis
Hematopoietic Stem Cells/metabolism
Humans
Intercellular Signaling Peptides and Proteins/metabolism
Lymphoid Progenitor Cells/cytology
Membrane Proteins/metabolism
Mice
Myeloid Progenitor Cells/cytology
Neovascularization, Physiologic
Pluripotent Stem Cells/cytology
Receptors, Notch/metabolism
Signal Transduction

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-04134-7

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Uenishi, G. I., Jung, H. S., Kumar, A., Park, M. A., Hadland, B. K., McLeod, E., Raymond, M., Moskvin, O., Zimmerman, C. E., Theisen, D. J., Swanson, S., J Tamplin, O., Zon, L. I., Thomson, J. A., Bernstein, I. D., & Slukvin, I. I. (2018). NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells. Nature communications, 9(1), 1828. https://doi.org/10.1038/s41467-018-04134-7

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, vol. 9, no. 1, pp. 1828. https://doi.org/10.1038/s41467-018-04134-7

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title = "NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells",

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.",

keywords = "Animals, Antigens, CD/immunology, Arteries/cytology, Calcium-Binding Proteins, Cell Differentiation, Cell Line, Cell Lineage, Cell Tracking/instrumentation, Coculture Techniques, Embryo, Mammalian/cytology, Endothelium, Vascular/cytology, Erythroid Precursor Cells/cytology, Hemangioblasts/cytology, Hematopoiesis, Hematopoietic Stem Cells/metabolism, Humans, Intercellular Signaling Peptides and Proteins/metabolism, Lymphoid Progenitor Cells/cytology, Membrane Proteins/metabolism, Mice, Myeloid Progenitor Cells/cytology, Neovascularization, Physiologic, Pluripotent Stem Cells/cytology, Receptors, Notch/metabolism, Signal Transduction",

author = "Uenishi, \{Gene I\} and Jung, \{Ho Sun\} and Akhilesh Kumar and Park, \{Mi Ae\} and Hadland, \{Brandon K\} and Ethan McLeod and Matthew Raymond and Oleg Moskvin and Zimmerman, \{Catherine E\} and Theisen, \{Derek J\} and Scott Swanson and \{J Tamplin\}, Owen and Zon, \{Leonard I\} and Thomson, \{James A\} and Bernstein, \{Irwin D\} and Slukvin, \{Igor I\}",

year = "2018",

month = may,

doi = "10.1038/s41467-018-04134-7",

language = "English (US)",

volume = "9",

pages = "1828",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

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T1 - NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells

AU - Uenishi, Gene I

AU - Jung, Ho Sun

AU - Kumar, Akhilesh

AU - Park, Mi Ae

AU - Hadland, Brandon K

AU - McLeod, Ethan

AU - Raymond, Matthew

AU - Moskvin, Oleg

AU - Zimmerman, Catherine E

AU - Theisen, Derek J

AU - Swanson, Scott

AU - J Tamplin, Owen

AU - Zon, Leonard I

AU - Thomson, James A

AU - Bernstein, Irwin D

AU - Slukvin, Igor I

PY - 2018/5

Y1 - 2018/5

N2 - 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.

AB - 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.

KW - Animals

KW - Antigens, CD/immunology

KW - Arteries/cytology

KW - Calcium-Binding Proteins

KW - Cell Differentiation

KW - Cell Line

KW - Cell Lineage

KW - Cell Tracking/instrumentation

KW - Coculture Techniques

KW - Embryo, Mammalian/cytology

KW - Endothelium, Vascular/cytology

KW - Erythroid Precursor Cells/cytology

KW - Hemangioblasts/cytology

KW - Hematopoiesis

KW - Hematopoietic Stem Cells/metabolism

KW - Humans

KW - Intercellular Signaling Peptides and Proteins/metabolism

KW - Lymphoid Progenitor Cells/cytology

KW - Membrane Proteins/metabolism

KW - Mice

KW - Myeloid Progenitor Cells/cytology

KW - Neovascularization, Physiologic

KW - Pluripotent Stem Cells/cytology

KW - Receptors, Notch/metabolism

KW - Signal Transduction

UR - http://europepmc.org/abstract/med/29739946

U2 - 10.1038/s41467-018-04134-7

DO - 10.1038/s41467-018-04134-7

M3 - Article

C2 - 29739946

SN - 2041-1723

VL - 9

SP - 1828

JO - Nature communications

JF - Nature communications

IS - 1

ER -

NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells

Abstract

Keywords

PubMed: MeSH publication types

UN SDGs

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