Project description:Chronic injury and inflammation pose high risks for epithelial dysplasia and cancer. In the “field cancerization” model, spontaneous mutations confer a stem-cell fitness advantage and promote gradual clonal expansion. Here, through 3d imaging, fate-mapping, biophysical modeling, and single-cell transcriptomics in a mouse model of acute colitis, we define an alternate, rapid mechanism for clonal expansion: the neutral activation of metabolically reprogrammed “founder progenitor cells” (FPCs) during wound healing. FPCs leverage the breakdown of normal crypt regenerative boundaries to expand multiplicatively into new crypts patterned from a zone of cellular mixing and plasticity. FPCs represent relatively generic proliferative cells probabilistically emerging from a background of fetal-reprogrammed epithelium and derive from both surface and basal zones of the injured colonic mucosa. Acute wound healing activates spatial and lineage plasticity to generate clonal fields without significant mutational burden. These results suggest that hallmark pre-neoplastic changes may arise from a punctuated pattern of injury and healing rather than gradual field cancerization.
Project description:The samples are a part of a study aiming at diagnosing ulcerative colitis from genome-wide gene expression analysis of the colonic mucosa. Colonic mucosal samples were collected as endoscopic pinch biopsies from ulcerative colitis patients and from control subjects. Samples with and without macroscopic signs of inflammation were collected from the patients. Experiment Overall Design: The series contain eight UC samples with macroscopic signs of inflammation, 13 UC smaples without macroscopic signs of inflammation, five control subjects.
Project description:Inflammatory bowel diseases (IBDs) including ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory diseases with increasing worldwide prevalence that show a perplexing heterogeneity in manifestations and response to treatment. We applied single cell RNA sequencing (scRNAseq) a to colonic tissue from a combined healthy, UC and CD cohort.
Project description:Colonoscopy biopsies from patients with ulcerative colitis were collected prior to biological therapy. The sampled mucosa was the area of active lesion. Heterogenety of the samples were studied.
Project description:BACKGROUND: Peroxisome proliferator-activated receptor g (PPAR g) is a nuclear receptor whose activation has been shown to modulate macrophage and epithelial cell-mediated inflammation. The objective of this study was to use a systems approach for investigating the mechanism by which the deletion of PPAR g in T cells modulates the severity of dextran-sodium sulfate (DSS)-induced colitis, immune cell distribution and global gene expression. METHODS: Wild-type (WT) or PPAR g flfl; CD4 Cre+ (CD4cre) mice in a C57BL/6 background were challenged with 2.5% DSS in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. RESULTS: Both disease severity and inflammation-related body weight loss were accelerated by the deficiency of PPAR g in T cells. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than wt mice and fewer CD4+FoxP3+ regulatory T cells (Treg) and IL10+CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated adhesion molecules on day 7 and proinflammatory cytokines interleukin-6 (IL-6) and IL-1b, and suppressor of cytokine signaling 3 (SOCS-3) mRNA expression. CONCLUSIONS: These findings suggest that T cell PPAR g down-regulates inflammation during DSS colitis by inhibiting colonic expression of inflammatory mediators and increasing MLN Treg. Colonic mucosa from wt and CD4cre mice were sampled at 0 (no DSS), 2, and 7 days of DSS-induced experimental colitis
Project description:Gene expression in the colonic mucosa of wild-type and p38a-knockout intestinal epithelial cells (IECs) were compared. C57BL/6 wild-type mice, and intestinal epithelial cell-specific p38a-knockout mice on a C57BL/6 background were used for isolation of colonic mucosa
Project description:These samples have been analyzed for global alternative splicing variation on exon-level expression data using the FIRMA algorithm. We have identified and described transcriptome instability as a genome-wide, pre-mRNA splicing related characteristic of solid cancers. This Series consists of 19 normal colonic mucosa samples from colorectal cancer patients, and is an amendment to a larger series of colorectal cancer and adjacent normal colonic mucosa samples analyzed for gene expression at the exon-level (GSE24550).
Project description:We compared the transcriptional signatures of the colonic mucosa from control mice (WT) versus mice deficient for the epithelial pantetheinase Vnn1 (Vnn1KO) or overexpressing Vnn1 specifically in intestinal epithelial cells (VIVA transgenic mice), during the development of DSS-induced colitis.