Targeting E-prostanoid 3 receptor ameliorates liver fibrosis through enhancing adhesion and cytotoxicity of NK cells toward HSCs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA807630 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18051529_1.fastq.gz | Fastqsanger.gz | |||
| SRR18051529_2.fastq.gz | Fastqsanger.gz | |||
| SRR18051530_1.fastq.gz | Fastqsanger.gz | |||
| SRR18051530_2.fastq.gz | Fastqsanger.gz | |||
| SRR18051531_1.fastq.gz | Fastqsanger.gz |
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Project description:Natural killer (NK) cells exhibit anti-fibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cell (HSC) populations. Prostaglandin (PG) E2 plays a dual role in innate and adaptive immunity. E-prostanoid 3 receptor (EP3) was markedly downregulated in NK cells from liver fibrosis mice and patients with liver cirrhosis. NK cell-specific deletion of EP3 aggravated hepatic fibrogenesis in mouse models of LF. For an in-depth analysis of the molecular alterations mediated by EP3 in NK cells, single-cell RNA sequencing (scRNA-seq) was performed using CD27+CD11b+ NK cells. GO, KEGG, GSEA revealed that the adhesion signaling pathway was downregulated in EP3-deficient NK cells. This phenotype was confirmed by qRT-PCR and function experiments. Thus, EP3 is required for adhesion and cytotoxicity of NK cells toward HSCs and may serve as a therapeutic target for the management of LF.
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Project description:Cigarette smoke causes diseases such as cardiovascular disorders. Heating tobacco, instead of burning, reduces consistently the amount of toxic compounds and may exert a reduced impact on cardiovascular health compared to cigarettes. Aqueous extract from the aerosol of a potential modified risk tobacco product, the carbon-heated tobacco product (CHTP) 1.2 was assessed in vitro for its impact, compared with a reference cigarette (3R4F), on a key mechanism of atherosclerosis, the adhesion of monocytic cells to artery endothelial cells. Human coronary arterial endothelial cells (HCAECs) were treated for 4h with conditioned media from monocytic Mono Mac-6 (MM6) cells exposed to the aqueous aerosol/smoke extracts for 2h (Indirect exposure) or directly with those extracts freshly generated (Fresh Direct exposure). Using a previously established in vitro adhesion assay design, MM6-HCAEC adhesion combined with inflammatory, oxidative stress, cytotoxicity and cell death markers was measured. The 3R4F extract promoted the adhesion of MM6 cells to HCAECs via distinct inflammatory- and cytotoxicity-driven mechanisms. In conclusions, our systems toxicology study demonstrated that approximately 10-15-fold higher concentrations of the CHTP1.2 aerosol extract were needed to elicit similar effects as the 3R4F smoke extract on cardiovascular disease-relevant inflammation and cytotoxicity-related mechanisms and markers investigated in vitro.
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Project description:introduction: Ageing is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia and malignancy results: We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programmes. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs in vivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. conclusion: Our results demonstrate that MMP is a source of heterogeneity in old HSCs and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.
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Project description:introduction: Ageing is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia and malignancy results: We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programmes. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs in vivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. conclusion: Our results demonstrate that MMP is a source of heterogeneity in old HSCs and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.
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