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Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic Hematopoietic stem cell fate [scRNA-seq]

ABSTRACT: Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium (HE) in the aorta- gonads-and mesonephros (AGM) region and reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch segregates these different fates are inconsistent. We now demonstrate that Notch activity is highest in a subset of, GFI1+, HSC-primed HE cells, and is gradually lost with HSC maturation. We uncover that the HSC phenotype is maintained due to increasing levels of NOTCH1 and JAG1 interactions on the surface of the same cell (cis) that renders the NOTCH1 receptor from being activated. Forced activation of the NOTCH1 receptor in IAHC activates a hematopoietic differentiation program. Our results indicate that NOTCH1-JAG1 cis-inhibition preserves the HSC phenotype in the hematopoietic clusters of the embryonic aorta.

ORGANISM(S): Mus musculus

PROVIDER: GSE230792 | GEO | 2024/01/22

REPOSITORIES: GEO

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Cis inhibition of NOTCH1 through JAGGED1 sustains embryonic Hematopoietic stem cell fate [RNA-seq]

Project description:Hematopoietic stem cells (HSCs) develop from the hemogenic endothelium (HE) in the aorta- gonads-and mesonephros (AGM) region and reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that distinguish HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch segregates these different fates are inconsistent. We now demonstrate that Notch activity is highest in a subset of, GFI1+, HSC-primed HE cells, and is gradually lost with HSC maturation. We uncover that the HSC phenotype is maintained due to increasing levels of NOTCH1 and JAG1 interactions on the surface of the same cell (cis) that renders the NOTCH1 receptor from being activated. Forced activation of the NOTCH1 receptor in IAHC activates a hematopoietic differentiation program. Our results indicate that NOTCH1-JAG1 cis-inhibition preserves the HSC phenotype in the hematopoietic clusters of the embryonic aorta.

2024-01-22 | GSE230790 | GEO

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.

2020-02-03 | GSE124477 | GEO

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

2020-01-10 | GSE124875 | GEO

Iterative single cell analyses define the transcriptome of the first functional hematopoietic stem cells

Project description:Whereas hundreds of endothelial cells in the aorta-gonad-mesonephros (AGM) region transdifferentiate to hematopoietic cells, only 1-2 of these cells take on hematopoietic stem cell (HSC) identity at a single time point. Gata2 is one of a few transcription factors essential for HSC generation and function. In contrast to cell surface marker-based HSC enrichment approaches, enrichment based on Gata2 expression is directly linked to the internal regulatory network critical for HSC identity. Here we use index sorting of highly enriched Gata2-expressing intra-aortic hematopoietic cluster (IAHC) cells, iterative single cell transcriptomics and functional analyses to examine the relationship between HSC identity and expression of pivotal factors. Functional HSCs are enriched in Gata2 medium-expressing IAHC cells, which can be further subdivided based on Gata2, cKit and CD27 expression, where each subpopulation is not only associated with a specific molecular profile, but also distinct functionality in both in vitro and in vivo stem/progenitor assays. Immunohistochemical analysis localizes the first putative functional HSCs in vivo to small clusters in the AGM region, thus integrating molecular, functional and spatial information about the first cells in a mammalian embryo that acquire full HSC identity.

2020-04-27 | GSE143637 | GEO

Pro-infammatory Aorta-Gonad-Mesonephros-associated macrophages are involved in embryonic development of hematopoietic stem cells

Project description:Hematopoietic stem cells (HSC) are generated from specialized endothelial cells of the embryonic aorta. Previously, inflammatory factors have been implicated in regulating mouse HSC development, but it is unclear what cells in the embryonic aorta-gonad- mesonephros (AGM) microenvironment produce these factors. In the adult, macrophages play both pro- and anti-inflammatory roles. We sought to examine whether macrophages or other hematopoietic cells found in the embryo prior to HSC generation are involved in the AGM HSC-generative microenvironment. Our CyTOF results indicate two abundant myeloid cell types - mannose-receptor positive AGM- associated macrophages (AGM-aM) and mannose-receptor negative macrophages/progenitors. We show that the appearance of macrophages in the AGM is dependent on CX3CR1. AGM-aM express a pro-inflammatory signature, localize to the embryonic aorta and dynamically interact with nascent and emerging intra-aortic hematopoietic cells (IAHC). Importantly, upon macrophage depletion, no adult- repopulating HSCs are detected, thus implicating unique pro-inflammatory AGM- associated macrophages in regulating the embryonic development of HSCs.

2019-06-01 | GSE130579 | GEO

Unravelling the heterogeneity of haemogenic endothelium in human pluripotent stem cell differentiation cultures

Project description:In embryo, few Endothelial cells from Aorta would be producing Haemogenic endothelium (HE) cells. These HE cells would then be progressing to take kind of a round shape and Undergo EHT. They then take a full round shape to make Intra-aortic haematopoietic clusters (IAHC) cells. These IAHC cells would then diassociate and turn into Hematopoitic Stem Cells (HSC) that ultimately would go to produce different lineage of hematopoitic (blood) cells. We wanted to study the heterogeneity of HE in human pluripotent stem cells.

2020-05-02 | E-MTAB-8271 | biostudies-arrayexpress

A critical requirement for IκBα in controlling dormancy in Hematopoietic stem cells via retinoic acid during embryonic development [scRNA-seq_10x]

Project description:Hematopoietic Stem Cells (HSCs) originate from the E11.5 aorta-gonads-and mesonephros (AGM) region during development before they migrate to the foetal liver for proliferation and maturation, and finally seed the bone marrow around birth, their final site of residence. In the AGM, HSCs reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). Molecular pathways that determine HSC fate instead of HPCs are still unknown, although inflammatory signalling has been implicated in the development of all blood cells, including NF-κB. Here, we describe a dormant phenotype of LT-HSCs in the IκBα KO. Although IκBα is critical for retaining inactive NF-κB complexes in the cytoplasm, it can regulate stem cell related genes by interacting with the PRC2 complex in the nucleus. Accordingly, we find decreased PRC2 dependent H3K27me3 accumulation at the promoters of PI3K and retinoic acid signalling molecules by cut and tag assay in AGM derived CD31+ cells, which includes HE/IAHC derived from IκBα KO embryos. Furthermore, this regulation of the retinoic acid signalling by IκBα is further confirmed by cut and tag assay for IκBα itself in CD31+ cells of the AGM and more specifically also in sorted LT-HSCs from the E14.5 foetal liver. Over-activation of the retinoic acid/PI3K levels in LT-HSCs of the IκBα KO is evident in their dormant molecular profile. Functionally, IκBα KO LT-HSCs are less proliferative and respond with delayed activation upon transplantation. Overall, we identify nuclear IκBα as an essential player specifically for HSC specification/proliferation from the onset of HSPC emergence in the AGM.

2024-04-15 | GSE214699 | GEO

A critical requirement for IκBα in controlling dormancy in Hematopoietic stem cells via retinoic acid during embryonic development [RNA-seq]

2024-04-15 | GSE188523 | GEO

A critical requirement for IκBα in controlling dormancy in Hematopoietic stem cells via retinoic acid during embryonic development [Cut&Tag]

2024-04-15 | GSE188524 | GEO

Bulk RNA sequencing and analysis of sorted fetal liver hematopoietic stem cells from VavCre+Jag1 f/f and WT E14.5 C57bl/6 embryos

Project description:We assesed the transcriptional profiles of sorted SLAM-LSK hematopoietic stem cells (HSCs) during expansion in the murine fetal liver from WT and Jag1-null mutants at embryonic day 14.5 post-conception. The goals of the study are to compare the expression profiles of rapidly proliferating fetal HSCs when the Notch ligand Jag1 is specifically deleted in the hematopoietic compartment. We find that hematopoietic deletion of Jag1 negatively impacts the expression of critical hematopoietic cell fate and identity genes such as GATA2, Mllt3 and Hoxa7. Our study establishes a unique role for Notch signaling activation in the fetal liver by the hematopoietic Jag1 ligand.

2023-07-25 | GSE186190 | GEO

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