Mapping Human Hematopoietic Stem Cells From Hemogenic Endothelium To Birth
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA683899 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13232946_1.fastq.gz | Fastqsanger.gz | |||
| SRR13232946_2.fastq.gz | Fastqsanger.gz | |||
| SRR13232947_1.fastq.gz | Fastqsanger.gz | |||
| SRR13232947_2.fastq.gz | Fastqsanger.gz | |||
| SRR13232948_1.fastq.gz | Fastqsanger.gz |
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Project description:Human hematopoietic stem cell (HSC) ontogeny is poorly defined due to the inability to identify HSCs as they emerge and mature in different hematopoietic sites. We created a single-cell transcriptome map of human hematopoietic tissues from 1st trimester to birth and found that HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the AGM (aorta-gonad-mesonephros) region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. Comparison of HSCs from different maturation stages revealed the establishment of HSC transcription factor machinery upon HSC emergence, whereas their surface phenotype evolved throughout development. HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens, reflecting nascent HSC identity, and acquisition of HSC maturity markers PROM1/CD133 and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+ hemogenic endothelial (HE) cells, which arose from IL33+ALDH1A1+ arterial endothelial subset, termed pre-HE. Spatial transcriptomics and immunofluorescence visualized this process in ventrally located intra-aortic hematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of AGM-like definitive HSPCs from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.
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Project description:The differentiation of human embryonic stem cells to hematopoietic lineages initiates with the specification of hemogenic endothelium, a transient specialized endothelial precursor of all blood cells.Unfortunately, absence of hemogenic endothelium-specific markers as well as lack of consensus in the timing of hemogenic potential analysis and methodologies used to study the hematopoietic potential of this precursor prevents reaching clear and definite conclusions. Here, we demonstrate that the hemogenic potential of the endothelium precursor population sharply decline over the course of the differentiation process. Poly(A) RNA-sequencing on CD31+CD144+ population at day 6, day 8 and day 10 of EB diffferentiation with or without the addition of cytokines. Comparasion with hematopoietic committed population CD31+CD144- from day 10 of EB differentiation.
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Project description:This SuperSeries is composed of the following subset Series: GSE25079: Epistasis analysis of Runx1 and Gata1 over HoxA3 in hemogenic endothelium GSE25080: Genes regulated by HoxA3 in endothelial and hematopoietic progenitors Refer to individual Series
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Project description:Previously, we reported that the transcription factor Mesp1 promotes the cell fates of cardiomyocytes, smooth muscle, and vascular endothelium. Recently, hematopoietic stem cells (HSCs) were shown to derive from hemogenic endothelium. Since Mesp1 regulates development of endothelium, it potentially could influence gene expression related to hematopoietic development. Our present fate mapping study found that Mesp1-cre efficiently labeled hematopoietic lineages in vivo. This result suggested that Mesp1 might be expressed in progenitors of the hematopoietic system, such as hemogenic endothelium. To test this, we purified Flk1+ Tie2+ endothelium derived from differentiating ES cells with or without Mesp1 induction, and used microarray expression analysis to identify genes strongly up-regulated by Mesp1. Embryonic stem (ES) cells harboring a doxycycline (dox)-inducible Mesp1 gene (A2lox.Mesp1) were differentiated as embryoid bodies for 5 days in the absence (-) or presence (+) of dox from day 2 to day 4. Flk1+Tie2+ endothelial cells were purified by cell sorting for RNA extraction and hybridization on Affymetrix microarrays.
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Project description:Scl/Tal1 confers hemogenic competence and prevents cardiomyogenesis in embryonic endothelium. Here we show that Scl both directly activates a broad gene regulatory network required for hematopoietic stem/progenitor cell (HS/PC) development, and represses transcriptional regulators required for cardiogenesis. Cardiac repression occurs during a short developmental window through Scl binding to distant cardiac enhancers that harbor H3K4me1 at this stage. Scl binding to hematopoietic regulators extends throughout HS/PC and erythroid development and spreads from distant enhancers to promoters. Surprisingly, Scl complex partners Gata 1 and 2 are dispensable for hematopoietic versus cardiac specification and Scl binding to the majority of its target genes. Nevertheless, Gata factors co-operate with Scl to activate selected transcription factors to facilitate HS/PC emergence from hemogenic endothelium. These results uncover a dual function for Scl in dictating hematopoietic versus cardiac fate choice and suggest a mechanism by which lineage-specific bHLH factors direct the divergence of competing fates. Examination of Scl and Gata 1 & 2 target genes in ES cell derived day4.75 EB (embryoid body) Tie2+CD31+CD41- endothelial cells
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Project description:Across species, hematopoietic stem and progenitor cells (HSPCs) arise during embryogenesis from a specialized arterial population, termed hemogenic endothelium. Here, we describe a mechanistic role for the epigenetic regulator, Enhancer of zeste homolog-1 (Ezh1) in vertebrate HSPC production via regulation of hemogenic commitment. Loss of ezh1 in zebrafish embryos favored acquisition of hemogenic (gata2b) and HSPC (runx1) fate at the expense of the arterial program (ephrinb2a, dll4). In contrast, ezh1 overexpression blocked hematopoietic progression via maintenance of arterial gene expression. The related polycomb group subunit, Ezh2, functioned in a non-redundant, sequential manner, whereby inhibition had no impact on arterial identity, but was capable of blocking ezh1-knockdown associated HSPC expansion. Single-cell RNA-seq across ezh1 genotypes revealed a dropout of ezh1+/- cells among arterial endothelium associated with positive regulation of gene transcription. Exploitation of Ezh1/2 modulation has potential functional relevance for improving in vitro HSPC differentiation from induced pluripotent stem cell sources.
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Project description:Scl/Tal1 confers hemogenic competence and prevents cardiomyogenesis in embryonic endothelium. Here we show that Scl both directly activates a broad gene regulatory network required for hematopoietic stem/progenitor cell (HS/PC) development, and represses transcriptional regulators required for cardiogenesis. Cardiac repression occurs during a short developmental window through Scl binding to distant cardiac enhancers that harbor H3K4me1 at this stage. Scl binding to hematopoietic regulators extends throughout HS/PC and erythroid development and spreads from distant enhancers to promoters. Surprisingly, Scl complex partners Gata 1 and 2 are dispensable for hematopoietic versus cardiac specification and Scl binding to the majority of its target genes. Nevertheless, Gata factors co-operate with Scl to activate selected transcription factors to facilitate HS/PC emergence from hemogenic endothelium. These results uncover a dual function for Scl in dictating hematopoietic versus cardiac fate choice and suggest a mechanism by which lineage-specific bHLH factors direct the divergence of competing fates. Examination of Scl and Gata 1 & 2 target genes in ES cell derived day4.75 EB (embryoid body) Tie2+CD31+CD41- endothelial cells
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Project description:Endothelium in embryonic hematopoietic tissues generates hematopoietic stem/progenitor cells; however, it is unknown how its unique potential is specified. We show that transcription factor Scl/Tal1 is essential for both establishing the hematopoietic transcriptional program in hemogenic endothelium and preventing its misspecification to a cardiomyogenic fate. Scl-/- embryos activated a cardiac transcriptional program in yolk sac endothelium, leading to the emergence of CD31+Pdgfrα+ cardiogenic precursors that generated spontaneously beating cardiomyocytes. Ectopic cardiogenesis was also observed in Scl-/- hearts, where the disorganized endocardium precociously differentiated into cardiomyocytes. Induction of mosaic deletion of Scl in Sclfl/flRosa26Cre-ERT2 embryos revealed a cell-intrinsic, temporal requirement for Scl to prevent cardiomyogenesis from endothelium. Scl-/- endothelium also upregulated the expression of Wnt antagonists, which promoted rapid cardiomyocyte differentiation of ectopic cardiogenic cells. These results reveal unexpected plasticity in embryonic endothelium such that loss of a single master regulator can induce ectopic cardiomyogenesis from endothelial cells.
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