Embryonic myeloid cells orchestrate niche cell homeostasis critical for the establishment of the definitive HSC pool [II]
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ABSTRACT:
PROVIDER: PRJNA1105057 | ENA |
REPOSITORIES: ENA
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Project description:The lifelong replenishment of blood cells relies on the function of definitive HSCs that migrate to the bone marrow during development. This process is tightly controlled by the bone marrow microenvironment. Embryonic macrophages emerge before the onset of definitive hematopoiesis, seed into discrete tissues and contribute to specialized resident macrophages throughout life. However, the functional impact of embryonic macrophages on HSCs or the niche remains unknown. Here, by taking advantage of a lineage tracer mouse tool we show that bone marrow macrophages consist of two ontogenetically distinct cell populations from embryonic and adult hematopoiesis. Mice lacking embryonic myeloid cells have decreased HSC numbers in the bone marrow accompanied by an increase of stem cells in the liver of neonate mice. The emergence of HSCs from embryonic sources is unperturbed because pre-HSC and HSC numbers are normal, suggesting a key role for embryo-derived myeloid cells in orchestrating HSC trafficking around birth. We show here that the establishment of a normal cellular niche space in the bone marrow critically depends on embryonic myeloid cells that are important for the development of mesenchymal stromal cells, but not other non-hematopoietic niche cells, providing evidence for a specific role for embryo-derived myeloid cells in the establishment of a normal niche environment pivotal for HSC homing.
2024-04-30 | GSE265827 | GEO
Project description:The lifelong replenishment of blood cells relies on the function of definitive HSCs that migrate to the bone marrow during development. This process is tightly controlled by the bone marrow microenvironment. Embryonic macrophages emerge before the onset of definitive hematopoiesis, seed into discrete tissues and contribute to specialized resident macrophages throughout life. However, the functional impact of embryonic macrophages on HSCs or the niche remains unknown. Here, by taking advantage of a lineage tracer mouse tool we show that bone marrow macrophages consist of two ontogenetically distinct cell populations from embryonic and adult hematopoiesis. Mice lacking embryonic myeloid cells have decreased HSC numbers in the bone marrow accompanied by an increase of stem cells in the liver of neonate mice. The emergence of HSCs from embryonic sources is unperturbed because pre-HSC and HSC numbers are normal, suggesting a key role for embryo-derived myeloid cells in orchestrating HSC trafficking around birth. We show here that the establishment of a normal cellular niche space in the bone marrow critically depends on embryonic myeloid cells that are important for the development of mesenchymal stromal cells, but not other non-hematopoietic niche cells, providing evidence for a specific role for embryo-derived myeloid cells in the establishment of a normal niche environment pivotal for HSC homing.
2024-05-01 | GSE265965 | GEO
Project description:Embryonic myeloid cells orchestrate niche cell homeostasis critical for the establishment of the definitive HSC pool
| PRJNA1104279 | ENA
Project description:The emergence of definitive human haematopoietic stem cells (HSCs) during Carnegie Stages (CS) 14-17 in the aorta-gonad-mesonephros (AGM) region is a complex and tightly regulated process. In a previous study we conducted spatial transcriptomic analysis of the human AGM region at the end of this period (CS16/17) and identified secreted factors involved in HSC development. Here, we extend our analysis to investigate the progression of dorso-ventral polarized signalling around the dorsal aorta over the entire period of HSC emergence. Our results reveal a dramatic increase in signalling complexity from the CS13 to CS14 transition, coinciding with the activation of endothelial-to-haematopoietic transition (EHT) in the ventral domain of the dorsal aorta. We further observe stage-specific changes in signalling complexity up to CS17. Signalling progression described here may underpin step-wise maturation of HSCs described in the mouse model. A data-rich bioinformatics resource presented here along with an interactive online interface enables in silico analysis of molecular interactions between spatially defined domains of the AGM region. This resource will be of particular interest for researchers studying mechanisms underlying human HSC development as well as those developing in vitro methods for the generation of clinically relevant HSCs from pluripotent stem cells.
2023-10-31 | GSE233126 | GEO
Project description:The emergence of definitive human haematopoietic stem cells (HSCs) during Carnegie Stages (CS) 14-17 in the aorta-gonad-mesonephros (AGM) region is a complex and tightly regulated process. In a previous study we conducted spatial transcriptomic analysis of the human AGM region at the end of this period (CS16/17) and identified secreted factors involved in HSC development. Here, we extend our analysis to investigate the progression of dorso-ventral polarized signalling around the dorsal aorta over the entire period of HSC emergence. Our results reveal a dramatic increase in signalling complexity from the CS13 to CS14 transition, coinciding with the activation of endothelial-to-haematopoietic transition (EHT) in the ventral domain of the dorsal aorta. We further observe stage-specific changes in signalling complexity up to CS17. Signalling progression described here may underpin step-wise maturation of HSCs described in the mouse model. A data-rich bioinformatics resource presented here along with an interactive online interface enables in silico analysis of molecular interactions between spatially defined domains of the AGM region. This resource will be of particular interest for researchers studying mechanisms underlying human HSC development as well as those developing in vitro methods for the generation of clinically relevant HSCs from pluripotent stem cells.
2023-10-31 | GSE233130 | GEO
Project description:Pluripotent stem cells (PSC) represent an alternative source of hematopoietic stem cells (HSCs). Clinical translation is impeded by limited engraftment of human (h)PSC-multipotent progenitor cells (MPP). This barrier suggests that additional cues are required for definitive hematopoiesis. We hypothesized that vascular niche producing Notch ligands Jagged-1 (JAG1) and Delta-like ligand-4 (DLL4) would drive definitive hematopoiesis. To test our hypothesis, hes2 human embryonic stem cells (hESC) 2 and Macaca nemestrina (Mn) iPSC line-7 were differentiated with cytokines ± endothelial cells (EC), which express JAG1 and DLL4. EC co-culture supported emergence of 8-fold more CD34+CD45+ cells compared to co-culture with cytokines ± ECs with JAG1 or DLL4 knockdown. EC-induced cells exhibit Notch activation and express HSC-specific targets of Notch signaling RUNX1 and GATA2. EC-induced PSC-MPP engraft at a higher level in NSG mice compared to cytokine-induced cells (10% >5 months), and selection increased engraftment (30%). Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction is similar to levels achieved for cord blood MPP and up to 20-fold higher than hPSC-MPP engraftment. Our findings identify a previously underappreciated role for endothelial Notch ligands in PSC definitive hematopoiesis and production of long-term engrafting CD34+ cells and suggest they are critical for HSC emergence. Transcriptome sequencing of Macaca nemestrina (Mn) iPSCs
2015-12-31 | E-GEOD-64644 | biostudies-arrayexpress
Project description:Multiple Niche Compartments Orchestrate Stepwise Stem Cell Lineage Differentiation
| PRJNA601761 | ENA
Project description:A comprehensive understanding of the genes and pathways regulating hematopoiesis is needed to identify genes causally related to bone marrow failure syndromes, myelodysplastic syndromes, and hematopoietic neoplasms. To identify novel genes involved in hematopoiesis, we performed an ethyl-nitrosourea mutagenesis screen in zebrafish (Danio rerio) to search for mutants with defective definitive hematopoiesis. We report the recovery and analysis of the grechetto mutant, which harbors an inactivating mutation in cleavage and polyadenylation specificity factor 1 (cpsf1), a gene ubiquitously expressed and required for 3' untranslated region processing of a subset of pre-mRNAs. grechetto mutants undergo normal primitive hematopoiesis and specify appropriate numbers of definitive HSCs at 36 hours postfertilization. However, when HSCs migrate to the caudal hematopoietic tissue at 3 days postfertilization, their numbers start decreasing as a result of apoptotic cell death. Consistent with Cpsf1 function, c-myb:EGFP(+) cells in grechetto mutants also show defective polyadenylation of snrnp70, a gene required for HSC development. By 5 days postfertilization, definitive hematopoiesis is compromised and severely decreased blood cell numbers are observed across the myeloid, erythroid, and lymphoid cell lineages. These studies show that cpsf1 is essential for HSC survival and differentiation in caudal hematopoietic tissue.
| S-EPMC3087528 | biostudies-literature
Project description:Mitochondrial metabolism determines bone marrow hematopoietic stem cell (HSC) heterogeneity, and influences long-term blood repopulation potential. However, when and how this mitochondrial regulation of definitive HSCs originates is unexplored. We 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 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 | GSE274538 | GEO