ScRNA-seq of human intestinal TRMs as well as intestinal organoids with autologous tissue-resident or blood derived immune compartment from 3 distinct donor samples
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PROVIDER: PRJEB76453 | ENA |
REPOSITORIES: ENA
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Project description:Molecular characterization of tissue-resident memory T cells cultured with or without donor-matched adult stem cell-derived intestinal organoids. Blood derived immune cells were also isolated and cultivated with autologous intestinal organoids for comparison and characterization. All conditions were derived from 3 human individuals and all samples were sequenced after 24h of in vitro culture. Data provides insights on circulating and tissue-resident immune cell populations, how these differentially interact with the epithelium and how these interactions shape both immune and epithelial cell states.
2024-06-27 | E-MTAB-14171 | biostudies-arrayexpress
Project description:Objective: The intestine occupies the critical interface between cholesterol absorption and excretion. Despite this, surprisingly little is known about the role of de novo cholesterol synthesis in this organ, and its relationship to whole body cholesterol homeostasis. In addition to cholesterol, the mevalonate pathway is responsible for the synthesis of numerous non-sterol isoprenoids. Here we investigate the physiological importance of the mevalonate pathway within the intestine, through genetic deletion of the rate-limiting enzyme. Approach and Results: Mice lacking 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) in intestinal villus and crypt epithelial cells were generated using a Villin-Cre transgene. In contrast to intestine-specific Srebp-2 and Scap knockouts, mice with intestinal-specific loss of Hmgcr are viable through adulthood and fertile. Hmgcr was efficiently deleted based on mRNA levels, as well as quantitative analysis of Hmgcr alleles by droplet digital PCR. Lipidomics revealed substantial reductions in the abundance of numerous non-sterol isoprenoids and sterol intermediates within the epithelial layer, while cholesterol levels were preserved. Although the intestinal knockout mice are born smaller, there is no net defect in feed efficiency or triglyceride absorption due to compensatory changes in bile acid composition and intestinal growth. At the cellular level, loss of Hmgcr is compensated for quickly after weaning through a dramatic expansion of the stem cell compartment within the crypts. Conclusions: Genetic loss of Hmgcr in the intestine is compatible with life, through mechanisms involving compensatory changes in bile acid composition, increased absorptive surface area, and expansion of the resident stem cell compartment.
2021-01-12 | GSE164589 | GEO
Project description:The intimate relationship between the epithelium and immune system is crucial for maintaining tissue homeostasis, with perturbations therein linked to autoimmune disease and cancer1-3. Whereas stem cell-derived organoids are powerful models of epithelial function4, they lack tissue-resident immune cells that are essential for capturing organ-level processes. We describe human intestinal immuno-organoids (IIOs), formed through self-organization of epithelial organoids and autologous tissue-resident memory T (TRM) cells, a portion of which integrate within the epithelium and continuously survey the barrier. TRM cell migration and interaction with epithelial cells was orchestrated by TRM cell-enriched transcriptomic programs governing cell motility and adhesion. We combined IIOs and single-cell transcriptomics to investigate intestinal inflammation triggered by cancer-targeting biologics in patients. Inflammation was associated with the emergence of an activated population of CD8+ T cells that progressively acquired intraepithelial and cytotoxic features. The appearance of this effector population was preceded and potentiated by a T helper-1-like CD4+ population, which initially produced cytokines and subsequently became cytotoxic itself. As a system amenable to direct perturbation, IIOs allowed us to identify the Rho pathway as a new target for mitigation of immunotherapy-associated intestinal inflammation. Given that they recapitulate both the phenotypic outcomes and underlying interlineage immune interactions, IIOs can be used to study tissue-resident immune responses in the context of tumorigenesis and infectious and autoimmune diseases.
| S-EPMC11374719 | biostudies-literature
Project description:Foxo1 regulates intestinal tissue-resident memory CD8 T cell biology in an anatomic compartment- and context-specific manner
| PRJNA1039504 | ENA
Project description:Intestinal deletion of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase promotes expansion of the resident stem cell compartment.
| PRJNA691272 | ENA
Project description:Intestinal homeostasis following postnatal microbial colonization requires the coordination of multiple processes, including the activation of immune cells, cell-cell communication, the controlled deposition of extracellular matrix, and epithelial cell turnover and differentiation. The intestine harbors the largest frequency of resident eosinophils of all homeostatic organs, yet the functional significance of eosinophil residence in the gut remains unclear. Eosinophils are equipped to both respond to, and modify, their local tissue environment and thus are able to regulate the adaption of tissues to environmental changes. We report a critical role for eosinophils in regulating villous structure, barrier integrity and motility in the small intestine. Notably, the microbiota was identified as a key driver of small intestinal eosinophil activation and function. Collectively our findings demonstrate a critical role for eosinophils in facilitating mutualistic interactions between host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.
2025-08-27 | PXD032084 | Pride
Project description:Transcriptional regulation of diverse aspects of tissue-resident CD8 memory T cells (TRM) biology is nuanced and context-specific. Transcription factors (TF) that orchestrate TRM formation and maintenance are distinct between anatomic compartments, and predicting the roles of TF on TRM biology is challenging. Here, we applied the Taiji algorithm to map TF networks and identify Forkhead Box protein 01 (Foxo1) as differentially invested in intestinal TRM TF networks. Loss of Foxo1 in established TRM resulted in a survival advantage for small intestinal intraepithelial layer (siIEL) TRM compared with other intestinal compartments. SiIEL TRM were uniquely able to maintain expression of proliferative and anti-apoptotic cellular programs in the absence of Foxo1. This advantage was lost upon blockade of integrin αE (Itgae/CD103). These findings suggest that the TF networks maintaining siIEL TRM exhibit redundancy and highlight an underappreciated role of integrin signaling in TRM biology outside of tissue-retention.
2025-04-11 | GSE247544 | GEO
Project description:Crypt hyperplasia is a key feature of celiac disease and various other small intestinal inflammatory conditions. By undertaking mass spectrometry-based tissue proteomics of the gut epithelial crypt zone, we found that active celiac disease is characterized by a strong interferon-γ (IFN-γ) signal. This signal, hallmarked by increased expression of MHC molecules, coincides with a markedly reduced expression of proteins associated with fatty acid metabolism. We observed similar crypt hyperplasia and proteomic alterations in wild-type mice treated with IFN-γ, but not in mice that lack the IFN-γ receptor in gut epithelial cells. IFN-γ is thus a driver of crypt hyperplasia in celiac disease by acting directly on crypt epithelial cells. This dataset contains proteomics analysis of crypt compartment samples isolated by laser capture microdissection small intestinal crypt compartment from C57/Bl6 mice injected i.p. with 0-1-2-4-6 or 9 doses interferon gamma every 8 hour.
2025-08-08 | PXD062684 | Pride
Project description:Using a novel fate-mapping approach, we identified that resident intestinal CD103 expressing T-cells lack secondary expansion potential and are replaced by de novo formed cells during re-infection.
2022-11-22 | GSE208097 | GEO
Project description:Resident human lamina propria immune cells serve as powerful effectors in host defense. Molecular events associated with the initiation of an intestinal inflammatory response in these cells are largely unknown. Here, we aimed to characterize phenotypic and functional changes induced in these cells at the onset of intestinal inflammation using a human intestinal organ culture model. In this model, healthy human colonic mucosa was depleted of epithelial cells by EDTA treatment. Following loss of the epithelial layer, expression of the inflammatory mediators IL-1β, IL-6, IL-8, IL-23p19, TNF-α, CXCL2 and the surface receptors CD14, TLR2, CD86, CD54 was rapidly induced in resident lamina propria cells in situ as determined by qRT-PCR and immunohistology. Gene microarray analysis of lamina propria cells obtained by laser-capture microdissection provided an overview of global changes in gene expression occurring during the initiation of an intestinal inflammatory response in these cells. Bioinformatic analysis gave insight into signalling pathways mediating this inflammatory response. Furthermore, comparison with published microarray datasets of inflamed mucosa in vivo (ulcerative colitis) revealed a significant overlap of differentially regulated genes underlining the in vivo relevance of the organ culture model. The organ culture model characterized may be useful to study molecular mechanisms underlying the initiation of an intestinal inflammatory response in normal mucosa as well as potential alterations of this response in inflammatory bowel disease. Gut specimens were derived from individuals undergoing resection for localized colon cancer. Microscopically normal colonic mucosa was dissected from the surgical specimen near the resection margin and immediately subjected to the experimental procedures. After extensive washing the mucus layer was removed by dithiothreitol (DTT) treatment. Subsequently, punches of defined surface area were prepared and denuded of epithelial cells by exposure to EDTA. Samples were collected prior to culturing and washing (control, t = 0 h, total mucosa, TM) as well as after loss of the epithelial layer (t = 5 h, mucosa after loss of epithelial layer, LEL-M) and snap frozen in liquid nitrogen. Lamina Propria (LP) was subsequently isolated via Laser Capture Microdissection (LMD) followed by RNA isolation. Microarray analysis of TM-LP (control) and LEL-LP samples was performed using the WG-DASL Human HT_12 V4 Expression BeadChip Assay from Illumina employing a minimum of 200 ng total RNA per sample. Four replicates from individual experiments were measured for each time point.
2014-04-03 | E-GEOD-56448 | biostudies-arrayexpress