Developing HSCs become Notch independent by the end of maturation in the AGM region

Souilhol, Céline; Lendinez, Javier G.; Rybtsov, Stanislav; Murphy, Fiona; Wilson, Heather M.; Hills, D.A.; Batsivari, Antoniana; Binagui-Casas, Anahí; McGarvey, Alison C.; MacDonald, H. Robson; Kageyama, Ryoichiro; Siebel, Christian W.; Zhao, Suling; Medvinsky, Alexander

doi:10.1182/blood-2016-03-708164

Cited by 55 publications

(62 citation statements)

References 90 publications

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“…These data support that both the phenotypic expansion and differentiation defect of Bloc1s2 À/À HSCs were attributed to hyperactivation of Notch signaling. Although a recent study showed that Notch signaling is independent of pre-HSC maturation in the AGM region [19], our data suggest that the balanced control of Notch activity by BLOS2 is essential for HSC maintenance in the FL.…”

Section: Resultscontrasting

confidence: 85%

BLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signaling

Gao

et al. 2017

Experimental Hematology

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Section: Resultscontrasting

confidence: 85%

BLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signaling

Gao

et al. 2017

Experimental Hematology

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“…When Dll4 is reduced, cells can proceed to the IAHC where HSC can be generated. Our interpretation is that several Notch signals are required for HSC development, likely coming from different ligands (Jag1 and Dll4) (Gama‐Norton et al , ), but also from different Notch receptors (Notch1 and Notch2) (Souilhol et al , ).…”

Section: Discussionmentioning

confidence: 95%

“…Notch receptors can be activated by different ligands either of the Jagged or Delta family of proteins. In the embryonic aortic endothelium, both types of ligands are expressed in a variety of cells and their interplay seems to be crucial to initiate the arterial and hematopoietic programs) (Krebs et al , ; Duarte et al , ; Robert‐Moreno et al , ; Souilhol et al , ).…”

Section: Introductionmentioning

confidence: 99%

Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation

et al. 2020

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Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium in cluster structures that protrude into the embryonic aortic lumen. Although much is known about the molecular characteristics of the developing hematopoietic cells, we lack a complete understanding of their origin and the three-dimensional organization of the niche. Here, we use advanced live imaging techniques of organotypic slice cultures, clonal analysis, and mathematical modeling to show the two-step process of intra-aortic hematopoietic cluster (IACH) formation. First, a hemogenic progenitor buds up from the endothelium and undergoes division forming the monoclonal core of the IAHC. Next, surrounding hemogenic cells are recruited into the IAHC, increasing their size and heterogeneity. We identified the Notch ligand Dll4 as a negative regulator of the recruitment phase of IAHC. Blocking of Dll4 promotes the entrance of new hemogenic Gfi1 + cells into the IAHC and increases the number of cells that acquire HSC activity. Mathematical modeling based on our data provides estimation of the cluster lifetime and the average recruitment time of hemogenic cells to the cluster under physiologic and Dll4-inhibited conditions.

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“…When Dll4 is reduced, cells can proceed to the IAHC where HSC can be generated. Our interpretation is that several Notch signals are required for HSC development, likely coming from different ligands (Jag1 and Dll4) 23 , but also from different Notch receptors (Notch1 and Notch2) 14 .…”

Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Notch ligand Dll4 impairs cell recruitment into aortic clusters and limits hematopoietic stem cells

Bigas

2019

Preprint

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Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium in cluster structures that protrude into the embryonic aortic lumen. Although much is known about the molecular characteristics of the developing hematopoietic cells, we lack a complete understanding of their origin and the three-dimensional organization of the niche. Here we use advanced live imaging techniques of organotypic slice cultures, clonal analysis, and mathematical modelling to show the two-step process of intra-aortic hematopoietic cluster (IACH) formation. First, a hemogenic progenitor buds up from the endothelium and undergoes division forming the monoclonal core of the IAHC. Next, surrounding hemogenic cells are recruited into the IAHC, increasing their size and heterogeneity. We identified the Notch ligand Dll4 as a negative regulator of the recruitment phase of IAHC. Blocking of Dll4 promotes the entrance of new hemogenic Gfi1+ cells into the IAHC and increases the number of cells that acquire HSC activity. Mathematical modelling based on our data provides estimation of the cluster lifetime and the average recruitment time of hemogenic cells to the cluster under physiologic and Dll4-inhibited conditions.

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Developing HSCs become Notch independent by the end of maturation in the AGM region

Abstract: Key Points Both Notch1 and Notch2 receptors are involved in pre-HSC maturation. Developing HSCs become Notch independent by the end of their maturation in the AGM region.

Cited by 55 publications

References 90 publications

BLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signaling

BLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signaling

Notch ligand Dll4 impairs cell recruitment to aortic clusters and limits blood stem cell generation

Notch ligand Dll4 impairs cell recruitment into aortic clusters and limits hematopoietic stem cells

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