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IFNa activates dormant HSCs in vivo

ABSTRACT: Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. Upon injury these cells are induced to proliferate in order to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNα), HSCs efficiently exit G0 and enter an active cell cycle. HSCs respond to IFNα treatment by increased phosphorylation of STAT1 and PKB/Akt, expression of IFNα target genes and up-regulation of stem cell antigen-1 (Sca-1). HSCs lacking either the interferon-α/β receptor (IFNAR), STAT1 or Sca-1 are insensitive to IFNα stimulation, demonstrating that STAT1 and Sca-1 mediate IFNα induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-FU1, HSCs pre-treated (primed) with IFNα and thus induced to proliferate are efficiently eliminated by 5-FU exposure in vivo. Conversely, HSCs chronically activated by IFNα are functionally compromised and are rapidly out competed by non-activatable IFNAR-/- cells in competitive repopulation assays. In summary, while chronic activation of the IFNα pathway in HSCs impairs their function, acute IFNα treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNα on leukemic cells and raise the possibility for novel applications of type I interferons to target cancer stem cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE14361 | GEO | 2009/01/15

SECONDARY ACCESSION(S): PRJNA111395

REPOSITORIES: GEO

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IFNa activates dormant HSCs in vivo

Project description:Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. Upon injury these cells are induced to proliferate in order to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNα), HSCs efficiently exit G0 and enter an active cell cycle. HSCs respond to IFNα treatment by increased phosphorylation of STAT1 and PKB/Akt, expression of IFNα target genes and up-regulation of stem cell antigen-1 (Sca-1). HSCs lacking either the interferon-α/β receptor (IFNAR), STAT1 or Sca-1 are insensitive to IFNα stimulation, demonstrating that STAT1 and Sca-1 mediate IFNα induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-FU1, HSCs pre-treated (primed) with IFNα and thus induced to proliferate are efficiently eliminated by 5-FU exposure in vivo. Conversely, HSCs chronically activated by IFNα are functionally compromised and are rapidly out competed by non-activatable IFNAR-/- cells in competitive repopulation assays. In summary, while chronic activation of the IFNα pathway in HSCs impairs their function, acute IFNα treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNα on leukemic cells and raise the possibility for novel applications of type I interferons to target cancer stem cells. cDNA microarray analysis was performed on sorted Lin neg, cKit+, CD150+, CD48neg HSCs from IFNα treated (16h after treatment) and untreated (littermate) mice. Per condition 3 independent biological replicates were analysed.

2009-01-15 | E-GEOD-14361 | biostudies-arrayexpress

Proteomic profiling of FAC-sorted ex vivo and in vitro expanded Sca-1+cells derived from murine skeletal muscle

Project description:Stem cells antigen-1 (Sca-1) is an 18-kDa mouse glycosyl phosphatidylinositol-anchored cell surface protein that has widely been used for isolation of murine hematopoietic stem cells (HSCs). However, recently several studies have reported the expression of this protein in non-HSCs such as the liver, skin and muscles among others. In the current study, we used fluorescence-activated cell sorting (FACS) technique to sort Sca-1+ stem cells from mouse hindlimb muscles. The Sca-1+ cells were divided into two sets first set of Sca-1+ cells were processed for protein extraction immediately after sorting (ex vivo set) while the second set of samples, referred to as in vitro set, were expanded in cell culture after sorting and harvested after two passage and then processed for protein extraction. A high-resolution proteome map of the ex vivo and in vitro sets was generated Orbitrap Fusion Tribrid Mass Spectrometer. In total, the analysis led to the identification of 5,581 protein groups.

2021-06-21 | PXD022247 | Pride

Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair

Project description:Bone marrow hematopoietic stem cells (HSCs) are crucial to maintain lifelong production of all blood cells. Although HSCs divide infrequently, it is thought that the entire HSC pool turns over every few weeks, suggesting that HSCs regularly enter and exit cell cycle. Here, we combine flow cytometry with label-retaining assays (BrdU and histone H2B-GFP) to identify a population of dormant mouse HSCs (d-HSCs) within the lin(-)Sca1+cKit+CD150+CD48(-)CD34(-) population. Computational modeling suggests that d-HSCs divide about every 145 days, or five times per lifetime. d-HSCs harbor the vast majority of multilineage long-term self-renewal activity. While they form a silent reservoir of the most potent HSCs during homeostasis, they are efficiently activated to self-renew in response to bone marrow injury or G-CSF stimulation. After re-establishment of homeostasis, activated HSCs return to dormancy, suggesting that HSCs are not stochastically entering the cell cycle but reversibly switch from dormancy to self-renewal under conditions of hematopoietic stress

2009-05-15 | GSE16100 | GEO

mRNA profiles of hematopoieitc stme cells treated with interferon gamma and/or vitronectin

Project description:Purpose: The goals of this study are to elucidate the influence of integrin β3 signaling on STAT1-dependnet gene expression in IFNγ-treated HSCs. Methods: Wild type (WT) HSCs were cultured with or without IFNγ and/or VN in the presence of stem cell factor (SCF) plus thrombopoietin (TPO). Subsequently, cultured HSC fraction (CD48- c-kit+ Sca-1+ Lineage-) were sorted, followed by mRNA sequence using Ion Proton (n>4). Moreover, to extract genes whose expression were changed via STAT1 in the presence of IFNγ, mRNA profiles of STAT1-/- HSCs treated with or without IFNγ were also generated by the same way. The sequence reads that passed quality filters were analyzed by CLC genomic workbench. Results: Using an optimized data analysis workflow, we mapped about 30 million sequence reads per sample to the mouse genome (build mm10) with CLC genomic workbench. Indeed, hierarchical clustering analysis showed that IFNγ-treated STAT1-/- HSCs was categorized to the group including Wt HSCs cultured in the absence of IFNγ rather than HSCs treated with IFNγ. Furthermore, gene set enrichment analysis (GSEA) showed that STAT1-dependent upregulated gene sets were significantly enriched within genes whose expression was enhanced in HSCs treated with VN and IFNγ. In contrast, integrin β3 signaling in the absence of IFNγ appears to not influence the expression of IFNγ/STAT1-dependent genes, as evidenced by the observation that VN treatment was statistically and significantly independent of the enrichment of gene sets that were both up-regulated by STAT1 Conclusions: Our study represents that STAT1 plays a central role in IFNγ-mediated HSC responses and integrin β3 signaling in HSCs promotes STAT1-dependent gene expression in the presence of IFNγ.

2017-06-01 | GSE81559 | GEO

Identification of targets regulated by SELP in HSC

Project description:To understand the underlying mechanism by which Alox15 gene is required by HSCs, we performed a comparative DNA microarray analysis using total RNA isolated from wild type Lin-Sca-1+c-Kit+, SELP-/- Lin-Sca-1+c-Kit+. The result was validated by quantitative real-time PCR analysis of wild type Lin-Sca-1+c-Kit+ and SELP-/- Lin-Sca-1+c-Kit+. Cancer stem cells are responsible for the initiation and maintenance of some types of cancer, and few effective target genes in these stem cells have been identified. Here we show that the selp is essential for the survival of leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML). To understand the underlying mechanism through which SELP regulates the function of HSCs, the gene expression profiles between WT and Selp-/- HSCs were compared. To understand the underlying mechanism through which SELP regulates the function of HSCs, the gene expression profiles between WT and Selp-/- HSCs were compared.

2014-05-09 | E-GEOD-57459 | biostudies-arrayexpress

BCR-ABL-mediated recruitment of STAT5 revealed by ChIPseq

Project description:Even in the era of ABL tyrosine kinase inhibitors, eradication of chronic myeloid leukemia (CML) stem cells still remains to be a prerequisite for the complete cure of the disease. Interferon-α (IFNα), which has been used long for the treatment for CML-chronic phase, are now being re-evaluated. However, the molecular mechanism involved in the action of IFNα on CML stem cells have not been elucidated yet. In this study we have found that IFNα upregulates CCAAT/Enhancer Binding Protein β (C/EBPβ), a transcription factor required for demand-driven granulopoiesis, through activation of STAT1 and STAT5 in BCR-ABL-expressing cells. Activated STAT1 and STAT5 were recruited to the newly identified 3’ distal enhancer region of Cebpb, which contains tandemly aligned interferon-g activated sequences (GAS). Genome editing-mediated repression or deletion of the GAS elements significantly abrogated the IFNα-dependent upregulation of C/EBPβ. IFNα induces differentiation and exhaustion of CML stem cells both in vitro and in vivo in a C/EBPβ-dependent manner. In addition, IFNα upregulates C/EBPβ and induces exhaustion of CD34+ CML stem cells obtained from CML patients. Collectively, these data clearly show that C/EBPβ is a critical factor in IFNα signaling that induces differentiation and exhaustion of CML stem cells.

2019-02-12 | GSE102809 | GEO

Discrimination of dormant and active hematopoietic stem cells by G0 markers reveals dormancy regulation by cytoplasmic calcium

Project description:Quiescent hematopoietic stem cells (HSCs) are typically dormant, and only a few quiescent HSCs are active. The relationship between “dormant” and “active” HSCs remains unresolved. Here we generated a G0 marker (G0M) mouse line that visualizes quiescent cells. G0M identifies a small population of active HSCs (G0Mlow), which are distinct from dormant HSCs (G0Mhigh), within the conventional quiescent HSC fraction. Single-cell RNA-Seq analyses showed that the gene expression profiles of these populations were nearly identical, yet differed in their Cdk4/6 activity. Furthermore high-throughput small molecule screening revealed that high concentrations of cytoplasmic calcium ([Ca2+]c) were linked to dormancy of HSCs. These findings indicate that G0M separates dormant and active adult HSCs, which are regulated by Cdk4/6 and [Ca2+]c. This G0M mouse line represents a useful resource for investigating physiologically important stem cell subpopulations.

2019-12-20 | GSE139013 | GEO

The response of murine primary airway epithelial cells to Influenza infection and the importance of Interferon type I signaling in this response [mAEC].

Project description:To investigate how murine airway epithelial cells respond to Influenza infection and how important interferon type I signaling is for this response, we harvested airway epithelial cells from the tracheas of wild type, interferon type I knockout(IFNaR-/-) and STAT1 knockout (STAT1-/-) mice and cultured them as previously described (Pickles et al,1998) in polarized airway epithelial cell cultures (mAECs). Triplicate mAECs from each type of mouse (wt,IFNaR-/-,STAT1-/-) were infected with 2X105 PFUs Influenza A (WSN) for 2h or mock inoculated and harvested 24h after infection. Triplicate murine polarized airway epithelial cell cultures from wild type, IFNaR-/- or STAT1-/- mice were mock treated or infected with 2x10^5 PFUs of Influenza A (WSN) for 2h and harvested 24 h post infection.

2012-03-12 | E-GEOD-32137 | biostudies-arrayexpress

Identification of targets regulated by SELP in HSC

2014-05-09 | GSE57459 | GEO

Gene expression profiling in WT and Hif1a-/- HSCs

Project description:To understand the underlying mechanism by which the Hif1a gene is required by hematopoietic stem cells (HSCs), we performed a comparative DNA microarray analysis using total RNA isolated from wild type Lin-Sca-1+c-Kit+ cells and Hif1a-/- Lin-Sca-1+c-Kit+ cells. The result was validated by quantitative real-time PCR analysis of wild type Lin-Sca-1+c-Kit+ and Hif1a-/- Lin-Sca-1+c-Kit+ cells. We compared the gene profile of HSCs between WT mice and Hif1a-/- mice.

2012-04-03 | E-GEOD-35110 | biostudies-arrayexpress

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