Intrinsic Xenobiotic Resistance of The Intestinal Stem Cell Niche
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA470664 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7139940_1.fastq.gz | Fastqsanger.gz | |||
| SRR7139940_2.fastq.gz | Fastqsanger.gz | |||
| SRR7139941_1.fastq.gz | Fastqsanger.gz | |||
| SRR7139941_2.fastq.gz | Fastqsanger.gz | |||
| SRR7139942_1.fastq.gz | Fastqsanger.gz |
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Project description:To characterize intestinal myofibroblasts that may contribute to the stromal compartment of the intestinal stem cell niche and identify possible causes of intrinsic xenobiotic resistance
2018-08-23 | GSE114249 | GEO
Project description:Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle may have. Here, we show that smooth muscle is the dominant supplier of BMP antagonists, which are niche factors that are essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate YAP. Together, we identify an important signaling axis that firmly establishes a role for smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem cell niche.
2021-11-02 | PXD025770 | Pride
Project description:Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle may have. Here, we show that smooth muscle is the dominant supplier of BMP antagonists, which are niche factors that are essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate YAP. Together, we identify an important signaling axis that firmly establishes a role for smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem cell niche.
2021-11-02 | PXD020561 | Pride
Project description:The intestine is an organ with exceptionally high rate of cell turnover and perturbations in this process can lead to disease such as cancer or intestinal atrophy. Nutrition is a key factor regulating the intestinal cell turnover and has a profound impact on intestinal volume and cellular architecture. However, how the intestinal equilibrium is maintained in fluctuating dietary conditions is insufficiently understood. By utilizing the Drosophila midgut as a model, we reveal a novel nutrient sensing mechanism coupling stem cell metabolism with stem cell extrinsic growth signal. Our results show that intestinal stem cells (ISCs) employ the hexosamine biosynthesis pathway (HBP) to monitor nutritional status and energy metabolism. Elevated activity of the HBP promotes Warburg effect-like metabolic reprogramming, which is required for the reactivation of ISCs from calorie restriction-induced quiescence. Furthermore, the HBP activity is an essential facilitator for insulin signaling-induced intestinal growth. In conclusion, intestinal stem cell intrinsic nutrient sensing regulates metabolic pathway activities, and defines the stem cell responsiveness to niche-derived growth signals.
2018-09-13 | GSE107052 | GEO
Project description:Wnt/b-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (PorcnDel/Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of PorcnDel organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable, and that stromal production of Wnts can fully support normal murine intestinal homeostasis. Microarray was performed on samples enriched for stromal or epithelial cells from small intestine from Porcn(Del)/Villin-Cre and Porcn(WT)/Villin-Cre male C57Bl/6 mice.
2014-04-19 | E-GEOD-56911 | biostudies-arrayexpress
Project description:Background & Aims: Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions. Methods: We generated mice with intestinal epithelial-specific disruption of Cul4b (pVillin-cre; Cul4bfn/Y), inducible disruption of Cul4b (Lgr5-creERT2; Cul4bfn/Y, CAG-creERT2; Cul4bfn/Y) and their control (Cul4bfn/Y). Intestinal tissues were analyzed by histology, immunofluorescence, RNA sequencing and mass spectrum. Intestinal organoids deprived from mice with pVillin-Cre; Cul4bfn/Y, Lgr5-Cre; Cul4bfn/Y, Tg-Cul4b and their controls were used in assays to measure intestinal self-renewal, proliferation and differentiation. Wnt signaling and intestinal markers were analyzed by immunofluorescence and immunoblot assays. Differential proteins upon Cul4b ablation or Cul4b-interacting proteins were identified by mass spectrometry. Results: Cul4b specifically located at ISCs zone. Block of Cul4b impaired intestinal homeostasis maintenance by reduced self-renewal and proliferation. Transcriptome analysis revealed that Cul4b-null intestine lose ISC characterization and showed disturbed ISC niche. Mechanistically, reactivated Wnt pathway could recover intestinal dysfunction of Cul4b knockout mice. Analysis of differential total and ubiquitylated proteins uncovered the novel targeting substrate of Cullin-Ring ubiquitin ligase 4b (CRL4b), immunity-related GTPase family M member 1 (Irgm1) in intestine. Decreased Irgm1 rescued abnormally interferon signaling, overemphasized autophagy and downstream phosphate proteins in Cul4b knockout mice. Conclusion: We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
2022-08-11 | PXD021528 | Pride
Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
2019-09-21 | E-MTAB-8340 | biostudies-arrayexpress
Project description:Wnt/b-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (PorcnDel/Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of PorcnDel organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable, and that stromal production of Wnts can fully support normal murine intestinal homeostasis.
2014-04-19 | GSE56911 | GEO
Project description:Intestinal stem cells are sequestered into crypts generated during postnatal development in mice. During this timeframe, we investigated the transition of the surrounding mesenchymal niche. Using single cell RNA sequencing, we generated transcriptomic libraries from a combination of whole tissue and transgenically labeled fractions, including GFP+ fractions from PdgfraH2BEGFP and GFP-tDt+ fractions from PdgfraH2BEGFP;Myh11CreERT2;Rosa26tDt+ mice, of the intestinal mesenchyme at varying postnatal and adult stages. We found distinct molecular signatures of these cell types, focusing our analysis on the temporal changes and known epithelial trophic factors.
2023-02-08 | GSE184158 | GEO
Project description:Pregnane X receptor (PXR), a xenobiotic receptor involved in drug metabolism, has been reported to regulate lipid and glucose metabolism. The intestine tract is the first inner barrier of the body, which dysfunction contributes to the development of metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. In this study, we showed that activation of PXR by tributyl citrate (TBC), an intestinal-selective agonist of PXR, improved high fat diet (HFD)-induced obesity and insulin resistance. The metabolic benefit of intestinal PXR activation was associated with upregulation of β-1,3 galactosyltransferase 5 (B3galt5). Our results revealed that B3galt5 is mainly expressed in the intestine and is a direct transcriptional target of PXR. Whole-body and intestine-specific knockout of B3galt5 exacerbated HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. Ablation of B3galt5 impaired the O-glycosylation of mucin2, destabilized the mucus layer, and increased the permeability of intestinal barrier. Furthermore, B3galt5 deficiency abolished the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggested the intestinal-selective activation of PXR regulated B3galt5 expression holds an important role in maintaining metabolic homeostasis, making it a potential therapeutic strategy in obesity.
2024-07-02 | GSE266942 | GEO