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Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [single-cell RNA-seq]

ABSTRACT: During ageing, cell-intrinsic and extrinsic factors lead to the decline of tissue function and organismal health. Disentangling these factors is important for developing effective strategies to prolong organismal healthspan. Here, we addressed this question in the mouse intestinal epithelium, which forms a dynamic interface with its microenvironment and receives extrinsic signals affecting its homeostasis and tissue ageing. We systematically compared transcriptional profiles of young and aged epithelial cells in vivo and ex vivo in cultured intestinal organoids. We found that all cell types of the aged epithelium exhibit an inflammation phenotype, which is marked by MHC class II upregulation and most pronounced in enterocytes. This was accompanied by elevated levels of the immune tolerance markers PD-1 and PD-L1 in the aged tissue microenvironment, indicating dysregulation of immunological homeostasis. Intestinal organoids from aged mice still showed an inflammation signature after weeks in culture, which was concurrent with increased chromatin accessibility of inflammation-associated loci. Our results reveal a cell-intrinsic, persistent inflammation phenotype in aged epithelial cells, which might contribute to systemic inflammation observed during ageing.

ORGANISM(S): Mus musculus

PROVIDER: GSE190848 | GEO | 2023/10/26

REPOSITORIES: GEO

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Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [in vivo bulk RNA-Seq]

Project description:During ageing, cell-intrinsic and extrinsic factors lead to the decline of tissue function and organismal health. Disentangling these factors is important for developing effective strategies to prolong organismal healthspan. Here, we addressed this question in the mouse intestinal epithelium, which forms a dynamic interface with its microenvironment and receives extrinsic signals affecting its homeostasis and tissue ageing. We systematically compared transcriptional profiles of young and aged epithelial cells in vivo and ex vivo in cultured intestinal organoids. We found that all cell types of the aged epithelium exhibit an inflammation phenotype, which is marked by MHC class II upregulation and most pronounced in enterocytes. This was accompanied by elevated levels of the immune tolerance markers PD-1 and PD-L1 in the aged tissue microenvironment, indicating dysregulation of immunological homeostasis. Intestinal organoids from aged mice still showed an inflammation signature after weeks in culture, which was concurrent with increased chromatin accessibility of inflammation-associated loci. Our results reveal a cell-intrinsic, persistent inflammation phenotype in aged epithelial cells, which might contribute to systemic inflammation observed during ageing.

2023-10-26 | GSE190082 | GEO

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [ATAC-Seq]

2023-10-26 | GSE190285 | GEO

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [ex vivo bulk RNA-Seq]

2023-10-26 | GSE190282 | GEO

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [Capture-C]

Project description:Low-grade chronic inflammation is considered a hallmark of ageing and associated with impaired tissue function and development of disease. However, how cell-intrinsic and -extrinsic factors interact to establish this phenotype, termed inflammaging, remains poorly understood. We addressed this question in the mouse intestinal epithelium, using organoid cultures to dissect stem cell-intrinsic and -extrinsic sources of increased inflammatory signaling upon ageing. At the single-cell level, we found that inflammaging establishes differently in cells along the crypt-villus axis, including intestinal stem cells (ISCs). Importantly, the inflammaging phenotype was stably propagated by aged ISCs in organoid cultures and associated with increased chromatin accessibility of inflammation-associated loci in vivo and ex vivo, indicating a cell-intrinsic memory of inflammation. Mechanistically, we show that expression of inflammaging genes is dependent on STAT1 signaling. Together, our data reveal that inflammaging in the intestine is promoted by a cell-intrinsic mechanism, stably propagated by ISCs and associated with a disbalance in immune homeostasis.

2023-10-26 | GSE233899 | GEO

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice [ATAC_invivo]

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RNA-seq of mouse small intestinal organoids with an intestinal-epithelial specific deletion of LSD1 compared to wild type

Project description:To assess the role of LSD1 in mouse small intestinal epithelium, we grew small intestinal organoids in vitro from mice with an epithelial specific deletion of LSD1 (Villin-Cre+; Lsd1f/f) and from wild type (Villin-Cre-; Lsd1f/f) mice. This experiment uses a new Cre strain with 100% recombination efficiency. Similar to intestinal epithelium from mice with an intestinal epithelium specific LSD1-KO, Paneth cells are not present in LSD1-KO small intestinal organoids. We used these sequencing data to show intrinsic epithelial changes in the intestinal epithelium caused by LSD1 deletion in the absence of microbiota and surrounding in vivo cell types.

2023-08-02 | E-MTAB-10500 | biostudies-arrayexpress

RNA-seq of small intestinal organoids treated with an inhibitor for the epigenetic modifier LSD1

Project description:To assess the role of LSD1 in mice small intestinal epithelium, small intestinal organoids were treated with an inhibitor for LSD1 (GSK-LSD1) and compared to untreated organoids. Similar to intestinal epithelium from mice with an intestinal epithelium specific LSD1-KO, paneth cells dissappear upon GSK-LSD1 treatment. We used these sequencing data to show that these small intestinal organoids have a similar phenotype as mice epithelium without LSD1.

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RNAseq of small intestinal organoids from mice treated with the cytokines IFNG, IL-13 and IL-22 for 24 hours

Project description:The intestinal epithelium is our first line of defense against infections of the gut and the plasticity in cellular differentiation of the intestinal epithelium is an important part of this response. The changes in cellular composition is driven by immune cell derived cytokines. Here we use signature cytokines of different type of immune responses applied to small intestinal organoids to model how different immune responses affect intestinal epithelial development. Simplified, IFNG represents type I immunity against intracellular pathogens such as viruses, IL-13 represents type II immunity against infections such as parasites and IL-22 represents type III immunity against extracellular bacterial infections. To not influence organoid formation, organoids were grown 24 hours without cytokines, and then 10 ng/mL of cytokine was applied for 24 hours before harvesting RNA. Furthermore, IFNG is supplied in combination with the other cytokines as cytokines are rarely found alone in an inflammation setting. We find that these cytokines affect developmental pathways of the intestinal epithelium and affect the cellular composition of the intestinal epithelium.

2022-05-08 | E-MTAB-9182 | biostudies-arrayexpress

Human small intestinal organoids grown with a specific protocol to enrich for Paneth cells were treated with an inhbitor (GSK-LSD1) for the epigenetic modulator LSD1.

Project description:To assess the role of LSD1 in human intestinal epithelium, human small intestinal organoids were treated with an inhibitor for LSD1 (GSK-LSD1) and compared to untreated organoids. The organoids were grown with specific conditions where Paneth cells are present in the organoids as similar experiments in mice show that Paneth cells disappear upon GSK-LSD1 treatment. Similar to mouse intestinal organoids, Paneth cells dissappear upon GSK-LSD1 treatment. Furthermore, we used these gene set enrichment analysis on these microarray data to show that these human intestinal organoids have a similar phenotype as mice epithelium without LSD1.

2020-11-16 | E-MTAB-7863 | biostudies-arrayexpress

Expression data from heterotopically grafted mouse small intestinal epithelium and the normal colonic epithelium

Project description:Epithelia of small and large intestines differ in their structures and functions. Such heterogeneity between these two epithelial tissues might be controlled by both epithelium-intrinsic and -extrinsic programs. By employing the cell transplantation technique developed in our laboratory, we investigated how adult SI epithelial cells behave when heterotopically transplanted onto colon. Then the gene expression profiles of small intestinal epithelium heterotopically transplanted onto colon and control colonic epithelium were compared. We used laser capture microdissection and microarray analysis to compare the global gene expression profiles of small intestinal epithelium in the heterotopically grafted tissues and control colonic epithelium. Dissected epithelia obtained from serial sections (~ 30 sections) of each specimen were combined and then total RNA extraction was performed. After calculating RNA Integrity Number (RIN), we subjected one graft sample and one control colon sample, which showed the highest RIN value, for the following gene expression analysis.

2014-08-15 | E-GEOD-59410 | biostudies-arrayexpress

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