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Notch ligand Dll4 impairs the recruitment of hemogenic cells into intra-aortic clusters and limits hematopoietic stem cell production

ABSTRACT: Notch ligand Dll4 impairs the recruitment of hemogenic cells into intra-aortic clusters and limits hematopoietic stem cell production

PROVIDER: PRJNA512128 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8377950.fastq.gz	Fastqsanger.gz
	SRR8377960.fastq.gz	Fastqsanger.gz
	SRR8377970.fastq.gz	Fastqsanger.gz
	SRR8377980.fastq.gz	Fastqsanger.gz
	SRR8377990.fastq.gz	Fastqsanger.gz

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Notch ligand Dll4 impairs the recruitment of hemogenic cells into intra-aortic clusters and limits hematopoietic stem cell production.

Project description:Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium in the embryonic aorta. In most vertebrates, hemogenic cells protrude into the aortic lumen forming clusters where the hematopoietic features are acquired. Although much is known about the molecular characteristics of the hematopoietic cells, we still lack basic understanding on the origin and 3D-organization of intraortic hematopoietic clusters (IAHC) in the mouse embryo and how they evolve over time. Here we use advanced live imaging techniques of organotypic slice cultures, clonal analysis, and mathematical modelling to show that IAHC formation is a two-step process. First, a hemogenic progenitor buds up from the endothelium and undergoes division forming the monoclonal core of the cluster. Next, cells from the surrounding hemogenic endothelium are recruited into the IAHCs, increasing their size and heterogeneity. We found that the recruitment phase of IAHC formation is negatively regulated by Notch signalling via the Delta-like-4 (Dll4) Notch ligand. We show that 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. Single cell transcriptomic analysis indicates that cell identities are preserved after Dll4 blockage. Our data provides for the first time a detailed characterization of the aortic hematopoietic stem cell niche and its maturation dynamics, identifying the Notch ligand Dll4 as a major molecular player governing dynamics of cluster formation and HSCs production.

2020-01-10 | GSE124875 | GEO

Notch ligand Dll4 impairs the recruitment of hemogenic cells into intra-aortic clusters and limits hematopoietic stem cell production

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Notch ligand Dll4 impairs the recruitment of hemogenic cells into intra-aortic clusters and limits hematopoietic stem cell production.

Project description:Notch ligand Dll4 impairs the recruitment of hemogenic cells into intra-aortic clusters and limits hematopoietic stem cell production.

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Identification of Notch ligand useage by splenic B cells using Dll1 and Dll4 Notch ligand blockade.

Project description:Marginal zone (MZ) B cells leverage Notch2 signals to attain rapid differentiation responses and positional cues with in the spenic environment.To determine the likely molecular source of Notch2 signals we sought to block the Notch ligands delta-like ligand 1 (Dll1) and delta-like ligand 4 (Dll4) in wildtype mice using in-vivo treatment with monoclonal blocking antibodies. Splenic populations of MZ B cells and follicular B cells were sort purified after 12, 24 and 48 hours of blockade and analyzed by RNA-seq.

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Gene expression profile of DLL4+ and DLL4- Hemato-Endothelial Progenitors (HEPs) subpopulations

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Gene expression profile of DLL4+ and DLL4- Hemato-Endothelial Progenitors (HEPs) subpopulations

Project description:In hESCs, expression of the Notch ligand DLL4 parallels the emergence of bipotent hematoendothelial progenitors (HEPs) and promotes their hematopoietic differentiation. During differentiation, DLL4 is only expressed in a subpopulation of HEPs. To study the developmental fate of the two subpopulations of HEPs identified by DLL4 expression, we FACS-isolated DLL4high and DLL4low/- HEPs at day 15 of differentiation and performed gene expression analysis using microarrays 10^5 DLL4high and DLL4low/- HEPs purified by FACS from H9 and AND1 hEBs at day 15 of hematopoietic differentiation were used for gene expression analysis using Whole Human Genome Oligo Microarray chips (Agilent Technologies).

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Identification of Notch ligand useage by splenic B cells using Dll1 and Dll4 Notch ligand blockade.

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

Project description: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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Project description:The lactate receptor GPR81 contributes to cancer development, yet the mechanisms remain unclear. Here, we show that GPR81 is upregulated in human cancers and further upregulated by extracellular lactate and three-dimensional growth of breast cancer spheroids. GPR81 knockdown (KD) increased spheroid necrosis and reduced invasion and in vivo tumor growth. GPR81 KD altered GO terms relating to extracellular matrix (ECM) and cell adhesion, including upregulation of Protocadherin-7 (PCDH7), which exhibited a striking, clustered expression in spheroids. Single cell analysis revealed that PCDH7 was inversely related with Ki-67 and co-clustered with other GPR81 KD-upregulated genes including Ephrin-type-A receptor-7 (EPHA7). The matricellular protein SPARC and the Notch ligand Delta-like-4 (DLL4), were downregulated upon GPR81 KD, and their KD elicited spheroid necrosis (DLL4) and inhibited invasion. We conclude that GPR81 supports breast cancer aggressiveness at least in part via SPARC and DLL4. Our findings substantiate GPR81 as a promising target in breast cancer treatment.

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