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STAT3 protects hematopoietic stem cells from intrinsic interferon signaling and loss of long-term blood-forming activity

ABSTRACT: STAT3 protects hematopoietic stem cells from intrinsic interferon signaling and loss of long-term blood-forming activity

PROVIDER: PRJNA909816 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22570421_1.fastq.gz	Fastqsanger.gz
	SRR22570421_2.fastq.gz	Fastqsanger.gz
	SRR22570422_1.fastq.gz	Fastqsanger.gz
	SRR22570422_2.fastq.gz	Fastqsanger.gz
	SRR22570423_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

STAT3 protects hematopoietic stem cells from intrinsic interferon signaling and loss of long-term blood-forming activity

Project description:The transcriptional regulator signal transducer and activator of transcription 3 (STAT3) has a well-established anti-inflammatory function in mature myeloid cells. This role, however, has precluded an understanding of STAT3 function in hematopoietic stem and progenitor cells (HSPCs), as Stat3 deletion in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. Thus, novel approaches to uncouple STAT3 function in HSPCs from the effects of systemic inflammation are needed. To address this, we established competitive mixed bone marrow (BM) chimeric mice with CreER-mediated conditional Stat3 deletion in 20% of the hematopoietic compartment. After confirming a lack of detectable inflammation in mice with Stat3-deficient BM, we found that, in contrast to Stat3-sufficient controls, Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM. Single-cell RNA sequencing of Lin-ckit+Sca1+ (LSKs) BM cells revealed an altered transcriptional landscape in Stat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, as evidenced by the intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation, Stat3-deficient LSKs accumulated γH2AX over time. Following secondary BM transplantation, Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.

2023-06-02 | GSE220466 | GEO

A Bartonella effector acts as signaling hub for intrinsic STAT3 activation to trigger anti-inflammatory responses

Project description:Chronically infecting pathogens avoid clearance by the innate immune system by promoting premature transition from an initial pro-inflammatory response towards an anti-inflammatory tissue-repair response. STAT3, a central regulator of inflammation, controls this transition and thus is targeted by numerous chronic pathogens. Here we show that BepD, an effector of the chronic bacterial pathogen Bartonella henselae targeted to infected host cells, establishes an exceptional pathway for canonical STAT3 activation, thereby impairing secretion of pro-inflammatory TNF-α and stimulating secretion of anti-inflammatory IL-10. Tyrosine phosphorylation of EPIYA-related motifs in BepD facilitates STAT3 binding and activation via c-Abl-dependent phosphorylation of Y705. The tyrosine-phosphorylated scaffold of BepD thus represents a signaling hub for intrinsic STAT3 activation that is independent from canonical STAT3 activation via transmembrane receptor-associated Janus kinases. We anticipate that our findings on a molecular shortcut to STAT3 activation will inspire new treatment options for chronic infections and inflammatory diseases.

2020-02-12 | PXD017119 | Pride

STAT3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis.

2010-10-20 | GSE18759 | GEO

B cell-intrinsic STAT3-mediated interferon suppression during murine gammaherpesvirus 68 infection revealed through in vivo competition model.[ccbr1030_Stat3_2019]

Project description:RNA-sequencing from sorted B cells of d16 infected mixed bone marrow chimeras. GC uninfected and GC infected samples of STAT3 WT and STAT3 KO B cells from 3 independent mixed bone marrow chimera experiments.

2023-12-01 | GSE227736 | GEO

B cell-intrinsic STAT3-mediated interferon suppression during murine gammaherpesvirus 68 infection revealed through in vivo competition model.[ccbr1030_Stat3_2021]

Project description:RNA-sequencing from sorted B cells of d16 infected mixed bone marrow chimeras. Non-GC, GC uninfected, and GC infected samples of STAT3 WT and STAT3 KO B cells from 3 independent mixed bone marrow chimera experiments.

2023-12-01 | GSE227764 | GEO

Mir-130a potentiates the reparative properties of human endothelial colony forming cells facing hypoxia via VEGFR2 and STAT3

Project description:Hypoxia controls reparative angiogenesis. MiRNAs are master regulators of gene expression in hypoxia and angiogenesis. However, we do not yet have a clear understanding of how hypoxia-induced miRNAs modulate vasoreparative processes. Here, we identify miR-130a as a mediator of the hypoxic response in human primary endothelial colony forming cells (ECFCs), a well-characterized subtype of endothelial progenitor. Under hypoxic conditions, miR-130a overexpression enhances ECFC pro-angiogenic capacity in vitro and potentiates their vasoreparative properties in vivo. Mechanistically, miR-130a orchestrates upregulation of VEGFR2, activation of STAT3-dependent transcription, and accumulation of HIF1α via translational inhibition of DDX6. These findings unveil a new role for miR-130a in hypoxia, whereby it modulates the VEGFR2/STAT3/HIF1α axis to increase the vasoregenerative capacity of ECFCs.

2022-12-06 | GSE142123 | GEO

STAT3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis

Project description:Background and aims: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6 type cytokine signaling required for hepatocyte proliferation and hepatoprotection but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. Methods: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2-/-) as a model for SC. Results: We demonstrate that conditional inactivation of stat3 in hepatocytes and cholangiocytes (stat3 delta hc) of mdr2-/- mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2-/- mice lacking IL-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both, hepatocytes and cholangiocytes. Loss of Stat3 in cholangiocytes led to increased expression of TNFÎ± which might reduce the barrier function of bile ducts. Loss of Stat3 in hepatocytes led to upregulation of bile acid biosynthesis genes and downregulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3deltahc mice were more sensitive to cholic acid-induced liver damage than control mice. Conclusions: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes. Affymetrix microarray analyses was performed to identify metabolic and molecular pathways in stat3Dhc mdr2-/- mice that lead to cholestasis and bile acid-induced liver injury. To avoid false positive results that are due to differential cellular composition, we defined the onset of fibrosis and expression of fibrogenic factors in stat3Dhc mdr2-/- mice.

2010-10-20 | E-GEOD-18759 | biostudies-arrayexpress

Proteomic analysis of the secretome from 4T1 breast cancer cells upon Stat3 silencing.

Project description:Stat3 has been acknowledged as an oncogene that has dual protumorigenic activity in a cell-intrinsic way, by promoting cancer cell proliferation and survival and in a paracrine mode, acting as suppressor of immune cell attack. We demonstrated that Stat3 silencing with a small interfering RNA (siRNA) induced a senescence program in Stat3-addicted cancer cells and leads to the production of a senescence associated secretory phenotype (SASP) that has several antitumor properties. The composition of the SASP induced by Stat3 silencing is poorly characterized. The goal of the project was to analyze the protein content in the secretome released by the mouse breast cancer cell line 4T1 after Stat3 silencing with a small interfering RNA.

2020-01-21 | PXD013948 | Pride

B cell-intrinsic STAT3-mediated interferon suppression during murine gammaherpesvirus 68 infection revealed through in vivo competition model.

Project description:B cell-intrinsic STAT3-mediated interferon suppression during murine gammaherpesvirus 68 infection revealed through in vivo competition model.

| PRJNA946778 | ENA

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation

Project description:A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation

| PRJNA1043569 | ENA