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Meis1 establishes the pre-hemogenic endothelial state prior to Runx1 expression II

ABSTRACT: Hematopoietic stem and progenitor cells (HSPCs) originate from an endothelial-to-hematopoietic transition (EHT) during embryogenesis. Characterization of early hemogenic endothelial (HE) cells is required to understand what drives hemogenic specification and to accurately define cells capable of undergoing EHT. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), we defined the early subpopulation of pre-HE cells based on both surface markers and transcriptomes. We identified the transcription factor Meis1 as an essential regulator of hemogenic cell specification in the embryo prior to Runx1 expression. Meis1 is expressed at the earliest stages of EHT and distinguishes pre-HE cells primed towards the hemogenic trajectory from the arterial endothelial cells that continue towards a vascular fate. Endothelial-specific deletion of Meis1 impaired the formation of functional Runx1-expressing HE which significantly impeded the emergence of pre-HSPC via EHT. Our findings implicate Meis1 in a critical fate-determining step for establishing EHT potential in endothelial cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE197400 | GEO | 2023/02/22

REPOSITORIES: GEO

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Meis1 establishes the pre-hemogenic endothelial state prior to Runx1 expression [CITE-seq]

Project description:Hematopoietic stem and progenitor cells (HSPCs) originate from an endothelial-to-hematopoietic transition (EHT) during embryogenesis. Characterization of early hemogenic endothelial (HE) cells is required to understand what drives hemogenic specification and to accurately define cells capable of undergoing EHT. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), we defined the early subpopulation of pre-HE cells based on both surface markers and transcriptomes. We identified the transcription factor Meis1 as an essential regulator of hemogenic cell specification in the embryo prior to Runx1 expression. Meis1 is expressed at the earliest stages of EHT and distinguishes pre-HE cells primed towards the hemogenic trajectory from the arterial endothelial cells that continue towards a vascular fate. Endothelial-specific deletion of Meis1 impaired the formation of functional Runx1-expressing HE which significantly impeded the emergence of pre-HSPC via EHT. Our findings implicate Meis1 in a critical fate-determining step for establishing EHT potential in endothelial cells.

2023-02-22 | GSE197244 | GEO

Meis1 establishes the pre-hemogenic endothelial state prior to Runx1 expression

2023-02-02 | GSE196047 | GEO

Depicting human endothelial to hematopoietic transition and the effects of modulating pyruvate catabolism on blood formation

Project description:Hematopoietic stem cell (HSC) quiescence, maintenance and differentiation are closely linked to changes in metabolism. However, the role of metabolism during the first emergence of HSCs from hemogenic endothelium (HE) is still unknown. In this study, we focus on the implication of energetic metabolic pathways during endothelial to hematopoietic transition (EHT). EHT is accompanied by a metabolic switch, with concomitant increases in glycolysis and oxidative phosphorylation (OXPHOS). Inhibiting glycolysis in HE cells leads to a block in hematopoietic lineage specification. An OXPHOS fuel, glutamine, is essential for HSC emergence and provides distinct intermediates to mediate differentiation towards the two major hematopoietic lineages, GPA+ and CD45+ cells. Strikingly, shifting the fate of pyruvate from glycolysis to the TCA cycle redirects HE specification towards CD45+ cells at the expense of GPA+ cells and vice versa. As such, our findings reveal the plasticity of hematopoietic lineage specification during EHT which can be modulated by metabolism.

2021-11-25 | GSE141189 | GEO

Whole-transcriptome analysis of endothelial-to-hematopoietic stem cell transition

Project description:Hematopoietic stem cells (HSCs) are generated via a natural transdifferentiation process known as endothelial-to-hematopoietic cell transition (EHT). Due to small numbers of embryonal arterial cells undergoing EHT and the paucity of markers to enrich for hemogenic endothelial cells, the genetic program driving HSC emergence is largely unknown. Here, we use a highly sensitive RNAseq method to examine the whole transcriptome of small numbers of enriched aortic HSCs (CD31+cKit+Ly6aGFP+), hemogenic endothelial cells (CD31+cKit-Ly6aGFP+) and endothelial cells (CD31+cKit-Ly6aGFP-). Comparison of mRNA profiles of endothelial cells, hemogenic endothelial cells, and hematopoietic stem cells generated by deep-sequencing of sorted populations from pool of embryos, in triplicate.

2014-12-14 | E-GEOD-63316 | biostudies-arrayexpress

N-Glycome regulation limits the transdifferentiation of endothelial cells into hematopoietic stem cells

Project description:Hematopoietic stem and progenitor cells (HSPCs) are required to establish and maintain the adult blood system in vertebrates. During development, HPSCs are generated from hemogenic endothelial cells that undergo an endothelial-to-hematopoietic transition (EHT). Growth factors and epigenetic changes can promote EHT, but these mechanisms do not explain its tight spatiotemporal regulation during development. Here, we show that microRNA (miR) miR-223-mediated regulation of N-glycan biosynthesis intrinsically restrains EHT, representing a new pathway that prevents excessive HSPC production. We find that miR-223 is uniquely expressed in hemogenic endothelial cells undergoing EHT and in nascent HSPCs. Loss of miR-223 promotes the expansion of these cells in the zebrafish and mouse aorta-gonad-mesonephros (AGM), where EHT occurs. miR-223 targets alg2 (alpha 1,3/ 1,6 mannosyltransferase) in the AGM endothelium to restrict hemogenic and HSPC specification. This enzyme is involved in the attachment of the N-glycans, a common co-translational modification9-12 that influences several pathophysiological processes, but has not yet been implicated in EHT. Using an N-glycosensor, we demonstrate that abundant protein N-glycan attachment occurs in vascular cells during EHT, and this process is required for HSPC production. High-throughput glycome analysis upon loss of miR-223 revealed that terminal alpha 1,3/6 mannose modifications are increased at the expense of alpha 2,3/6 sialic acid sugars. Importantly, pharmacological manipulation targeting these N-glycan types in wild-type embryos phenocopies the loss of miR-223 and enhances EHT as well as HSPC production. Thus, the N-glycome plays a previously unappreciated role as an intrinsic regulator of EHT, with specific mannose and sialic acid modifications serving as key endothelial determinants to restrict the hematopoietic fate.

2021-09-09 | GSE135246 | GEO

Expression data from developing hematopoietic stem and progenitor cells

Project description:In the mouse embryo during midgestation, hematopoietic stem cells (HSCs) are generated from aortic endothelium through the transdifferentiation process known as endothelial-to-hematopoietic transition, or EHT. During EHT, flat-shaped hemogenic endothelium transform into round-shaped hematopoietic cells, which subsequently form cell aggregates, called hematopoietic clusters. To understand HSC specification during ontogeny and to search for nascent HSC markers, we performed single-cell microarray analysis of developing HSC populations.

2019-05-01 | GSE113892 | GEO

System-wide Dissection of the Transcriptional Response to RUNX1 During Hematopoietic Specification [ChIP-seq]

Project description:The specification of hematopoietic cells in the developing embryo occurs in specific stages and is regulated by the successive establishment of specific transcriptional networks. However, the molecular mechanisms of how the different stages switch from one to another are still not well understood. Hematopoietic cells arise from endothelial cells within the dorsal aorta which transit into hematopoietic cells by a process called the endothelial-hematopoietic transition (EHT) which does not involve DNA replication. The transcription factor RUNX1 is essential for this process. Using the differentiation of mouse embryonic stem cells carrying an inducible version of RUNX1, we have previously shown that hematopoietic genes are primed prior to the EHT by the binding of transcription factors required to form both endothelial and hematopoietic cells (FLI-1 and SCL/TAL1). We demonstrated that after induction RUNX1 reshapes the transcription factor binding landscape by causing a relocation of these factors and pulling them towards its binding sites. In the study presented here, we employed the same system to globally dissect the transcriptional processes that underlay the EHT. We demonstrate that the RUNX1-mediated movement of FLI-1 involves the recruitment of the basal transcription components CDK9 and BRD4 to promoters. The looping factor LDB1 to binds to distal elements and after induction relocates towards RUNX1/FLI-1 to form a co-localizing complex in chromatin. This entire process is blocked by treatment with the BRD4 inhibitor JQ1. Our study constitutes a paradigm for transcriptional processes driving transitions in cellular shape and function which are widely observed in development and disease.

2018-07-19 | GSE104045 | GEO

System-wide Dissection of the Transcriptional Response to RUNX1 During Hematopoietic Specification [RNA-seq]

2018-07-19 | GSE104044 | GEO

Whole-transcriptome analysis of endothelial-to-hematopoietic stem cell transition

2014-12-14 | GSE63316 | GEO

Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming

Project description:During development, hematopoietic stem/progenitor cells (HSPCs) arise from specialized endothelial cells by a process termed endothelial-to-hematopoietic transition (EHT). The genetic program driving human HSPC emergence remains largely unknown. We previously reported that the generation of hemogenic precursor cells from mouse fibroblasts recapitulates developmental hematopoiesis. Here, we demonstrate that human fibroblasts can be reprogrammed into hemogenic cells by the same transcription factors. Induced cells display dynamic EHT transcriptional programs, generate hematopoietic progeny, possess HSPC cell surface phenotype and repopulate immunodeficient mice for three months. Mechanistically, GATA2 and GFI1B interact and co-occupy a cohort of targets. This cooperative binding is reflected by engagement of open enhancers and promoters, initiating silencing of fibroblast genes and activating the hemogenic program. However, GATA2 displays dominant and independent targeting activity during the early phases of reprogramming. These findings shed light on the processes controlling human HSC specification and support generation of reprogrammed HSCs for clinical applications.

2018-12-04 | GSE51025 | GEO

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