Pro-infammatory Aorta-Gonad-Mesonephros-associated macrophages are involved in embryonic development of hematopoietic stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE130579 | GEO | 2019/06/01
REPOSITORIES: GEO
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Project description:Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from the AGM, FL and BM. Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive line from Fetal Calvaria (OP9) and non-supportive stromal clones from fetal liver (BFC). Hematopoietic stem cells (HSCs) are at the basis of the hematopoietic hierarchy. Their ability to self-renew and differentiate is strictly controlled by molecular signals produced by their surrounding micorenvironments composed of stromal cells. HSCs first emerge in the AGM (Aorta Gonads Mesonephros) region, amplify in the fetal liver (FL) and are maintained in the adult bone marrow (BM). To further characterize the molecular program of the HSC niches, we have compared the global transcriptome of HSC-supportive and non-supportive stromal clones established from fetal liver. We took advantage of stromal clones established from the AGM, FL and BM and tested for their ability to support or not HSCs ex vivo. RNA were extracted from confluent stromal cultures or sorted cells and used for hybridization of Affymetrix (mouse gene 1.0 ST) microarrays.
2014-03-01 | E-GEOD-44181 | biostudies-arrayexpress
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 | GSE230792 | GEO
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
Project description:Many pathways regulating blood formation have been elucidated, yet how each coordinates with embryonic biophysiology to modulate the spatio-temporal production of hematopoietic stem cells (HSCs) is currently unresolved. Here, we report that glucose metabolism impacts the onset and magnitude of HSC induction in vivo. In zebrafish, transient elevations in physiological glucose levels elicited dose-dependent effects on HSC development, including enhanced runx1 expression and hematopoietic cluster formation in the Aorta-Gonad-Mesonephros (AGM) region; embryonic-to-adult transplantation studies confirmed glucose increased functional HSCs. Glucose uptake was required to mediate the enhancement in HSC development; likewise, metabolic inhibitors diminished nascent HSC production and reversed glucose-mediated effects on HSCs. Increased glucose metabolism preferentially impacted hematopoietic and vascular targets, as determined by gene expression analysis, through mitochondrial-derived reactive oxygen species (ROS)-mediated stimulation of hypoxia inducible factor 1α (hif1α); epistasis assays demonstrated hif1α regulates HSC formation in vivo and mediates the dose-dependent effects of glucose metabolism on the timing and magnitude of HSC production. We propose this fundamental metabolic-sensing mechanism enables the embryo to respond to changes in environmental energy input and adjust hematopoietic output to maintain embryonic growth and ensure viability. We performed microarray analysis to explore the changes in gene expression that occur in repsonse to altered metabolism during the induction of developmental hematopoeisis. We compared RNA from zebrafish raised in a solution of 1% glucose from 12-36hpf vs controls. Two biological replicates for each condition were performed.
2013-02-15 | E-GEOD-43186 | biostudies-arrayexpress
Project description:Mitochondrial metabolism determines bone marrow hematopoietic stem cell (HSC) heterogeneity, and influences long-term blood repopulation potential.Self-renewal and multilineage engraftment capacity of hematopoietic stem cells (HSCs) are key properties leveraged for their clinical use in bone marrow transplantation. Variations in long-term blood reconstitution ability are partly attributed to the functional heterogeneity in HSCs, which is influenced by the dynamic mitochondrial metabolic state, in addition to differences in gene expression. However, when and how this mitochondrial regulation of definitive HSCs originates is unexplored. Whether metabolic variation is an outcome of the diverse HSC milieu, or an inherent property of the emergent HSCs, is not known. Here, Wwe show that dynamic changes in mitochondrial activity during endothelial to hematopoietic transition (EHT) drives the production of mature HSCs in the mouse embryo. Pharmacological and genetic manipulations show that hematopoietic emergence during the endothelial to hematopoietic transition (EHT) in the aorta-gonad-mesonephros (AGM) region involves mitochondrial remodelling. reduced mitochondrial activity activates Wnt signalling to promote expansion of mature HSCs in the AGM. Further, single cell transcriptomics and functional assays uncovered mitochondrial membrane potential (MMP) driven functional heterogeneity within the mature HSC pool. MMPlow HSCs are myeloid-biased and exhibit enhanced differentiation potential. Contrarily, MMPhigh HSCs are lymphoid-biased with diminished differentiation potential. Mechanistically, low mitochondrial activity upregulates PI3K signalling to fuel embryonic HSC differentiation. We provide insights into the metabolic regulation of HSC origin and function, that can be leveraged to direct HSC fate decisions for clinical interventions.
2024-08-27 | GSE274537 | GEO
Project description:Transcriptome analysis of adult hematopoietic stem cells (HSC) and their progeny has informed our understanding of blood differentiation and leukemogenesis, but a similarly transformative analysis of the embryonic origins of hematopoiesis is lacking. To address this issue, we acquired gene expression profiles of developing HSC purified from over 2500 dissected murine embryos and adult mice, and applied a network biology-based analysis to reconstruct the gene regulatory networks of sequential stages of HSC development. We found that embryonic hematopoietic elements clustered into three distinct transcriptional states characteristic of the definitive yolk sac, HSCs emerging from hemogenic endothelium, and definitive HSCs. We functionally validated several candidate transcriptional regulators of HSC ontogeny by morpholino-mediated knock-down in zebrafish embryos, confirming changes in the expression of HSC markers runx1 and c-myb in the aorta-gonads-mesonephros (AGM), the site of definitive HSC specification. Moreover, we found that HSCs derived from differentiating embryonic stem cells in vitro (ESC-HSC) most closely resemble definitive HSC, yet lack a signature indicative of specification by Notch signaling, which likely accounts for their deficient lymphoid development. Our analysis and accompanying web resource will accelerate the characterization of regulators of HSC ontogeny, facilitate efforts to direct hematopoietic differentiation and cell fate conversion, and serve as a model to study the origins of other adult stem cells. Hematopoietic stem cells and their precursors were isolated from mouse embryos and distinct stages and sites during development, purified by fluorescence activated cell sorting, and gene expression profiled on Affymetrix arrays. We also profiled HSCs and their precurors derived by in vitro differentitation of embryonic stem cells [expression data from GSE16925 and GSE14012 was used for mESCs, available at http://hsc.hms.harvard.edu/].
2012-11-01 | E-GEOD-37000 | biostudies-arrayexpress
Project description:The first HSCs are produced in the aorta-gonadmesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production/expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture. Embryonic day 11 AGM are dissected and either analyzed directly, or after explant culture in conditions containing BMP/Hedgehog with or without cyclopamine. EC: endothelial enriched (CD31+Kit-); MC: mesenchymal cell enriched (CD31-Kit-); HPSC: hematopoietic progenitor/stem cell enriched; AGM11: E11 fresh AGMs; AGMex: AGM after explant culture; AGMcy: AGM after explant in presence of cyclopamine; CD31p: CD31 positive; CD31n: CD31 negative; KITp: c-Kit positive; KITn: c-Kit negative; BREp: BRE-GFP positive; BREn: BRE-GFP negative
2015-12-22 | E-GEOD-76253 | biostudies-arrayexpress
Project description:Many pathways regulating blood formation have been elucidated, yet how each coordinates with embryonic biophysiology to modulate the spatio-temporal production of hematopoietic stem cells (HSCs) is currently unresolved. Here, we report that glucose metabolism impacts the onset and magnitude of HSC induction in vivo. In zebrafish, transient elevations in physiological glucose levels elicited dose-dependent effects on HSC development, including enhanced runx1 expression and hematopoietic cluster formation in the Aorta-Gonad-Mesonephros (AGM) region; embryonic-to-adult transplantation studies confirmed glucose increased functional HSCs. Glucose uptake was required to mediate the enhancement in HSC development; likewise, metabolic inhibitors diminished nascent HSC production and reversed glucose-mediated effects on HSCs. Increased glucose metabolism preferentially impacted hematopoietic and vascular targets, as determined by gene expression analysis, through mitochondrial-derived reactive oxygen species (ROS)-mediated stimulation of hypoxia inducible factor 1α (hif1α); epistasis assays demonstrated hif1α regulates HSC formation in vivo and mediates the dose-dependent effects of glucose metabolism on the timing and magnitude of HSC production. We propose this fundamental metabolic-sensing mechanism enables the embryo to respond to changes in environmental energy input and adjust hematopoietic output to maintain embryonic growth and ensure viability.
2013-02-15 | GSE43186 | GEO
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.
2022-01-20 | GSE162950 | GEO
Project description:Mouse hematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5) on the ventral surface of the dorsal aorta, by endothelial-to-hematopoietic transition (EHT). We investigated whether cells with mesenchymal stem cell-like cell (MSC-LCs) activity that provide an essential niche for HSCs in the bone marrow reside in the aorta-gonad-mesonephros (AGM) and contribute to the structural development of the dorsal aorta and EHT. Using transgenic mice, we demonstrate a lineage hierarchy for AGM MSC-LCs and trace the aortic endothelium and HSCs to mesoderm-derived (Mesp1) PDGFRA+ cells. Mesp1/PDGFRA+ MSC-LCs dominate the sub-endothelial and ventral stroma in the E10.5–E11.5 AGM but by E13.5 are replaced by neural crest (Wnt1) MSC-LCs. Co-aggregating endothelial cells with Mesp1 but not with Wnt1 MSC-LCs resulted in EHT and generation of LT-HSCs that is interrupted by dose-dependent inhibition of PDGFRA signalling. This partnership between endothelial cells and AGM Mesp1 MSC-LCs could be harnessed to manufacture HSCs from endothelium.
2022-04-26 | GSE163757 | GEO