Single-cell analysis of colonic organoids deficient for tumor necrosis factor receptor 2
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ABSTRACT:
PROVIDER: PRJNA962604 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24330233_1.fastq.gz | Fastqsanger.gz | |||
| SRR24330233_2.fastq.gz | Fastqsanger.gz | |||
| SRR24330234_1.fastq.gz | Fastqsanger.gz | |||
| SRR24330234_2.fastq.gz | Fastqsanger.gz | |||
| SRR24330235_1.fastq.gz | Fastqsanger.gz |
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Project description:Our study reports a role for mesenchymal TNFR1 in maintaining colonic mesenchymal cell diversity and facilitation of a function epithelial stem cell niche. Through RNA-seq profiling, we show that a TNFR1-deficient mesenchyme has altered anchoring and cell substrate junctions, focal adhesions, extracellular matrix, and actin binding processes. We find specific reduction in the key stem cell niche factor, RSPO3, crucial for Lgr5+ stem cell maintenance, downregulated 5.1-fold in the TNFR1 deficient mesenchyme. Pathways classically associated with proliferation and differentiation, including Phosphoinositide 3-kinase (P13k) and Mitogen-activated protein kinase (MAPK), and those involved in migration, namely Ras-proximate-1 or Ras-related protein 1 (RAP1), TGF-β and RAS, were significantly enriched in TNFR1-/- mesenchyme compared to controls. In particular, Itga6, representing the integrin alpha 6 subunit, was one of the most highly upregulated transcripts. Therefore, the transcriptome profiling of the TNFR1 deficient mesenchyme deletion suggests an important role for TNFR1 in the regulation of mesenchymal cell-matrix interactions and niche transcript expression.
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Project description:Colonic epithelial repair is a key determinant of health. After injury, repair initiates through phenotypic reprogramming of wounded epithelium to a regenerative state permissive for the activation of alternative stem cell populations and healing. Although cytokine signals such as interferons may help induce regenerative reprogramming, the signals that modify this state as the wound resolves remain largely unknown. Here we examined whether cytokine signaling mediated by tumor necrosis factor receptor 2 (TNFR2) influenced the wound repair process. We examined mice with targeted deletion of the Tnfrsf1b (TNFR2) gene in intestinal/colonic epithelium (Vil1::Cre;Tnfr2-f/f) and compared their transcriptional profiles to control (Tnfr2-f/f) mice. We sorted EpCAM+ (epithelial) cells from Vil1::Cre;Tnfr2-f/f and control DSS-treated mice and performed bulk RNA-Seq. Comparison of transcript expression profile before and after DSS-induced colitis in control (Tnfr2-f/f) mice revealed upregulation of pathways associated with metabolic regulation, ribosomal function, oxidative stress, TNF signaling, and focal adhesions after DSS treatment. Pathway enrichment analysis demonstrated elevated regenerative (“fetal”) intestinal signaling, reduced inflammation, and increased proliferative signaling in Vil1::Cre;Tnfr2-f/f colonic epithelium after DSS treatment. The knockout epithelium also showed reduced expression of markers of differentiated colonic epithelium and elevated expression of progenitor cell signaling. Thus, the transcriptional data were consistent with increased regenerative signaling in TNFR2-knockout epithelium, suggesting that TNFR2 has a role in restraining the relatively undifferentiated regenerative state.
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