Single-cell multiomics of human fetal hematopoiesis defines a developmental specific population and a fetal signature
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ABSTRACT:
PROVIDER: PRJNA793904 | ENA |
REPOSITORIES: ENA
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Project description:Knowledge of human fetal blood development and how it differs from adult is highly relevant to our understanding of congenital blood and immune disorders and childhood leukemia, of which the latter can originate in utero. Blood formation occurs in waves that overlap in time and space adding to heterogeneity, which necessitates single-cell approaches. Here, a combined single cell immunophenotypic and transcriptional map of first trimester primitive blood development is presented. Using CITE-seq (Cellular-Indexing-of-Transcriptomes-and-Epitopes-by-Sequencing) the molecular profile of established immunophenotypic gated progenitors was analyzed in the fetal liver (FL). Classical markers for hematopoietic stem cells (HSCs) such as CD90 and CD49F were largely preserved, whereas CD135 (FLT3) and CD123 (IL3R) had a ubiquitous expression pattern capturing heterogenous populations. Direct molecular comparison with an adult bone marrow (BM) dataset revealed that the HSC state was less frequent in FL, whereas cells with lympho-myeloid signature were more abundant. An erythro-myeloid primed multipotent progenitor cluster was identified, potentially representing a transient, fetal-specific population. Furthermore, differentially expressed genes between fetal and adult counterparts were specifically analyzed, and a fetal core signature identified. The core gene set could separate subgroups of Acute Lymphoblastic Leukemia (ALL) by age, suggesting that a fetal program may be partially retained in specific sub-groups of pediatric leukemia. Our detailed single-cell map presented herein emphasizes molecular and immunophenotypic differences between fetal and adult blood cells, of significance for future studies of pediatric leukemia and blood development in general.
2023-06-28 | GSE192966 | GEO
Project description: Not available
| S-EPMC10506049 | biostudies-literature
Project description:Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1 null hematopoietic lineage. The Becn1-STAT3-ISG15 axis remains functional in Atg5/7-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3-ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.
2025-05-07 | PXD057003 | Pride
Project description:Hematopoiesis in Murine Fancd2-/- vs WT Fetal Liver
| PRJNA727546 | ENA
Project description:The hierarchical organization of hematopoietic stem cells (HSCs) governing adult hematopoiesis has been extensively investigated. However, the dynamic epigenomic transition from fetal to adult hematopoiesis remains incompletely understood, particularly regarding the involvement of epigenetic factors. In this study, we investigate the roles of BRD9, an essential component of the non-canonical BAF (ncBAF) complex known to govern the fate of adult HSCs, in fetal hematopoiesis. Consistent with observations in adult hematopoiesis, BRD9 loss impairs fetal HSC stemness and disturbs erythroid maturation. Intriguingly, the impact on myeloid lineage was discrepant: BRD9 loss inhibited and promoted myeloid differentiation in fetal and adult models, respectively. Through comprehensive transcriptomic and epigenomic analyses, we elucidate the differential roles of BRD9 in a context- and lineage-dependent manner. Our data uncover how BRD9/ncBAF complex modulates transcription in a stage-specific manner, providing deeper insights into the epigenetic regulation underlying the transition from fetal to adult hematopoiesis.
2025-02-21 | GSE269139 | GEO
Project description:The hierarchical organization of hematopoietic stem cells (HSCs) governing adult hematopoiesis has been extensively investigated. However, the dynamic epigenomic transition from fetal to adult hematopoiesis remains incompletely understood, particularly regarding the involvement of epigenetic factors. In this study, we investigate the roles of BRD9, an essential component of the non-canonical BAF (ncBAF) complex known to govern the fate of adult HSCs, in fetal hematopoiesis. Consistent with observations in adult hematopoiesis, BRD9 loss impairs fetal HSC stemness and disturbs erythroid maturation. Intriguingly, the impact on myeloid lineage was discrepant: BRD9 loss inhibited and promoted myeloid differentiation in fetal and adult models, respectively. Through comprehensive transcriptomic and epigenomic analyses, we elucidate the differential roles of BRD9 in a context- and lineage-dependent manner. Our data uncover how BRD9/ncBAF complex modulates transcription in a stage-specific manner, providing deeper insights into the epigenetic regulation underlying the transition from fetal to adult hematopoiesis.
2025-02-21 | GSE269138 | GEO
Project description:The hierarchical organization of hematopoietic stem cells (HSCs) governing adult hematopoiesis has been extensively investigated. However, the dynamic epigenomic transition from fetal to adult hematopoiesis remains incompletely understood, particularly regarding the involvement of epigenetic factors. In this study, we investigate the roles of BRD9, an essential component of the non-canonical BAF (ncBAF) complex known to govern the fate of adult HSCs, in fetal hematopoiesis. Consistent with observations in adult hematopoiesis, BRD9 loss impairs fetal HSC stemness and disturbs erythroid maturation. Intriguingly, the impact on myeloid lineage was discrepant: BRD9 loss inhibited and promoted myeloid differentiation in fetal and adult models, respectively. Through comprehensive transcriptomic and epigenomic analyses, we elucidate the differential roles of BRD9 in a context- and lineage-dependent manner. Our data uncover how BRD9/ncBAF complex modulates transcription in a stage-specific manner, providing deeper insights into the epigenetic regulation underlying the transition from fetal to adult hematopoiesis.
2025-02-21 | GSE269137 | GEO
Project description:The hierarchical organization of hematopoietic stem cells (HSCs) governing adult hematopoiesis has been extensively investigated. However, the dynamic epigenomic transition from fetal to adult hematopoiesis remains incompletely understood, particularly regarding the involvement of epigenetic factors. In this study, we investigate the roles of BRD9, an essential component of the non-canonical BAF (ncBAF) complex known to govern the fate of adult HSCs, in fetal hematopoiesis. Consistent with observations in adult hematopoiesis, BRD9 loss impairs fetal HSC stemness and disturbs erythroid maturation. Intriguingly, the impact on myeloid lineage was discrepant: BRD9 loss inhibited and promoted myeloid differentiation in fetal and adult models, respectively. Through comprehensive transcriptomic and epigenomic analyses, we elucidate the differential roles of BRD9 in a context- and lineage-dependent manner. Our data uncover how BRD9/ncBAF complex modulates transcription in a stage-specific manner, providing deeper insights into the epigenetic regulation underlying the transition from fetal to adult hematopoiesis.
2025-02-21 | GSE278845 | GEO
Project description:Ribosomopathies are associated with anemia; yet, the precise control of ribosomal protein (RP) stoichiometry and activity during erythroid development remains elusive. Using Diamond-Blackfan anemia (DBA) as a model, we generated novel in vivo models of RP haploinsufficiency to define the roles of small and large RP subunits in fetal hematopoiesis. Rpl5 haploinsufficiency caused prenatal lethality due to a reduction in erythroid translation. Conversely, Rps19 haploinsufficiency led to neonatal stem cell exhaustion and impaired erythroid progenitor expansion, resulting from combined translational and transcriptional defects. The stem cell factor RUNX1 is upregulated in RPS19-haploinsufficient DBA patients and its deletion partially rescued hematopoiesis in Rps19 mutant mice. Our findings reveal distinct, subunit-specific roles for RPs in fetal hematopoiesis and demonstrate that imbalanced RP stoichiometry disrupts developmental programs, providing key insights into DBA pathogenesis and patient heterogeneity while underscoring the importance of balanced RP expression in stem cell and erythroid progenitor development.
2026-03-05 | GSE304205 | GEO
Project description:Ribosomopathies are associated with anemia; yet, the precise control of ribosomal protein (RP) stoichiometry and activity during erythroid development remains elusive. Using Diamond-Blackfan anemia (DBA) as a model, we generated novel in vivo models of RP haploinsufficiency to define the roles of small and large RP subunits in fetal hematopoiesis. Rpl5 haploinsufficiency caused prenatal lethality due to a reduction in erythroid translation. Conversely, Rps19 haploinsufficiency led to neonatal stem cell exhaustion and impaired erythroid progenitor expansion, resulting from combined translational and transcriptional defects. The stem cell factor RUNX1 is upregulated in RPS19-haploinsufficient DBA patients and its deletion partially rescued hematopoiesis in Rps19 mutant mice. Our findings reveal distinct, subunit-specific roles for RPs in fetal hematopoiesis and demonstrate that imbalanced RP stoichiometry disrupts developmental programs, providing key insights into DBA pathogenesis and patient heterogeneity while underscoring the importance of balanced RP expression in stem cell and erythroid progenitor development.
2026-03-05 | GSE302344 | GEO