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High levels of canonical Wnt signaling lead to loss of stemness and increased differentiation in hematopoietic stem cells

ABSTRACT: Canonical Wnt signalling regulates the self-renewal of most if not all stem cell systems. In the blood system, the role of Wnt signalling has been subject of much debate, with positive and negative roles of Wnt signalling proposed for hematopoietic stem cells (HSC). As we have shown previously, this controversy can be largely explained by the effects of different dosages of Wnt signalling. What remained unclear however, was why high Wnt signals would lead to loss of reconstituting capacity. To better understand this phenomenon, we have taken advantage of a series of hypomorphic mutant Apc alleles resulting in a broad range of Wnt dosages in HSCs, purified those HSCs and performed whole genome gene expression analyses. Gene expression profiling and functional studies show that HSCs with APC mutations lead to high Wnt levels , enhanced differentiation and diminished proliferation, but have no effect on apoptosis, collectively leading to loss of stemness. Thus, we provide mechanistic insight into the role of APC mutations and Wnt signalling in HSC biology. As Wnt signals are explored in various in vivo and ex vivo expansion protocols for HSCs, our findings also have clinical ramifications.

ORGANISM(S): Mus musculus

PROVIDER: GSE79495 | GEO | 2016/03/23

SECONDARY ACCESSION(S): PRJNA315992

REPOSITORIES: GEO

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High levels of canonical Wnt signaling lead to loss of stemness and increased differentiation in hematopoietic stem cells

Project description:Canonical Wnt signalling regulates the self-renewal of most if not all stem cell systems. In the blood system, the role of Wnt signalling has been subject of much debate, with positive and negative roles of Wnt signalling proposed for hematopoietic stem cells (HSC). As we have shown previously, this controversy can be largely explained by the effects of different dosages of Wnt signalling. What remained unclear however, was why high Wnt signals would lead to loss of reconstituting capacity. To better understand this phenomenon, we have taken advantage of a series of hypomorphic mutant Apc alleles resulting in a broad range of Wnt dosages in HSCs, purified those HSCs and performed whole genome gene expression analyses. Gene expression profiling and functional studies show that HSCs with APC mutations lead to high Wnt levels , enhanced differentiation and diminished proliferation, but have no effect on apoptosis, collectively leading to loss of stemness. Thus, we provide mechanistic insight into the role of APC mutations and Wnt signalling in HSC biology. As Wnt signals are explored in various in vivo and ex vivo expansion protocols for HSCs, our findings also have clinical ramifications. To investigate the effects of Wnt signals in hematopoietic cells, mice carrying floxed Apc or hypomorphic Apc mutants were crossed, LSK cells were isolated and treated with Cre IRES GFP gamma-retrovirus ex vivo, GFP+ cells were sorted and RNA expression was determined.

2016-03-23 | E-GEOD-79495 | biostudies-arrayexpress

Role of c-Myc haploinsufficiency in the maintenance of HSCs

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Mitochondrial activity dictates definitive hematopoietic stem cell production and lympho-myeloid lineage segregation during mouse embryogenesis [scRNAseq]

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Mitochondrial activity dictates definitive hematopoietic stem cell production and lympho-myeloid lineage segregation during mouse mouse embryogenesis [bulkRNAseq]

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

Parallel spatial transcriptomics, single-cell and bulk RNA-Seq analysis of the human embryonic HSC niche, the dorsal aorta

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The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS

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Project description:Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence resulting in severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.

2017-09-13 | PXD006054 | Pride

The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS

2010-02-21 | E-GEOD-20352 | biostudies-arrayexpress

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