Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis
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ABSTRACT:
PROVIDER: PRJNA430822 | ENA |
REPOSITORIES: ENA
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Project description:The intestinal epithelium is a highly structured tissue composed of repeating crypt-villus units. Enterocytes, which constitute the most abundant cell type, perform the diverse tasks of absorbing a wide range of nutrients while protecting the body from the harsh bacterial-rich environment. It is unknown if these tasks are equally performed by all enterocytes or whether they are spatially zonated along the villus axis. Here, we performed whole-transcriptome measurements of laser-capture-microdissected villus segments to extract a large panel of landmark genes, expressed in a zonated manner. We used these genes to localize single sequenced enterocytes along the villus axis, thus reconstructing a global spatial expression map. We found that most enterocyte genes were zonated. Enterocytes at villi bottoms expressed an anti-bacterial Reg gene program in a microbiome-dependent manner, potentially reducing the crypt pathogen exposure. Translation, splicing and respiration genes steadily decreased in expression towards the villi tops, whereas distinct mid-top villus zones sub-specialized in the absorption of carbohydrates, peptides and fat. Enterocytes at the villi tips exhibited a unique gene-expression signature consisting of Klf4, Egfr, Neat1, Malat1, cell adhesion and purine metabolism genes. Our study exposes broad spatial heterogeneity of enterocytes, which could be important for achieving their diverse tasks.
2018-02-07 | GSE109413 | GEO
Project description:The protective and absorptive functions of the intestinal epithelium rely on differentiated enterocytes in the villi. The differentiation of enterocytes is orchestrated by sub-epithelial mesenchymal cells producing distinct ligands along the villus axis, in particular Bmps and Tgf. Here we show that individual Bmp ligands and Tgf drive distinct enterocytic programs specific to villus zonation. Bmp4 is expressed mainly from the centre to the upper part of the villus, and it activates preferentially genes connected to lipid uptake and metabolism. In contrast, Bmp2 is produced by villus-tip mesenchymal cells, and it influences the adhesive properties of villus-tip epithelial cells and the expression of antimicrobial peptides. Hence, Bmp2 promotes the terminal enterocytic differentiation at the villus-tip. Additionally, Tgf induces an epithelial gene expression programs similar to that triggered by Bmp2. The inhibition of Bmp receptor type I in vivo and using intestinal organoids lacking Smad4 revealed that Bmp2-driven villus-tip program is activated by a canonical Smad-dependent mechanism. Finally, we established an organoid cultivation system that enriches for villus-tip enterocytes and thereby better mimics the cellular composition of the intestinal epithelium. Altogether our data suggest that not only Bmp gradient, but also the activity of individual Bmp drives specific enterocytic programs.
2023-07-01 | GSE216699 | GEO
Project description:Small intestinal villi are highly specialized structural and functional units uniquely adapted to the absorption of nutrients in higher vertebrates. Intestinal villus enterocytes are organized in spatially resolved “zones” dedicated to specialized tasks, such as anti-bacterial protection, and absorption of amino-acids, carbohydrates and lipids. However, the molecular mechanisms for the establishment and maintenance of villus intestinal epithelial zonation are incompletely understood. Here, we show that transcription factor C-Maf is highly expressed in mature lower and mid-villus small intestinal enterocytes, where it is induced in response to BMP signaling. In vivo depletion of C-Maf in the adult enterocytes perturbed the villus epithelial zonation transcriptional program and enhanced the expression of genes involved in carbohydrate metabolism and bile acid regulation and transport, while suppressing genes related to amino acid transport and lipid metabolism. Loss of C-Maf under homeostatic conditions had no effect on body weight due to compensatory small intestinal remodeling, accompanied by increased generation of tuft cells and goblet cell hyperplasia. However, upon challenge with anti-metabolite therapy, C-Maf inactivation impaired body weight recovery, resulting in reduced survival, due to delayed enterocyte maturation. Our results identify a novel role for C-Maf in maintaining the zonation program of differentiated intestinal epithelium, by balancing absorptive versus secretory cell differentiation in the small intestine, while highlighting the importance of coordination between stem/progenitor cell and enterocyte differentiation programs for intestinal regeneration.
2022-08-18 | GSE189852 | GEO
Project description:We analyzed gene expression profiles in isolated mouse LGR5+ intestinal stem cells, lineage-specific enterocyte and secretory progenitors, and terminally differentiated villus enterocytes. Gene Ontology analyses of cell type-specific transcripts indicated their expected biological functions. We hybridized Affmetrix 430A 2.0 mouse microarrays with processed RNA isolated from purified Lgr5+ intestinal stem cells, secretory (Sec-Pro) and enterocyte (Ent-Pro) crypt progenitors, and mature villus enterocytes (ENT).
2014-01-06 | E-GEOD-51398 | biostudies-arrayexpress
Project description:Transcriptional profiling of jejunal gene expression during the differentiation from crypt to villus cells in rats, using cryostat sections of the villus-crypt columns.
2009-04-05 | GSE15421 | GEO
Project description:Genes encoding transcription factors function as hubs in gene regulatory networks because they encode DNA-binding proteins, which bind to promoters that carry their binding sites. In the present work we have studied gene regulatory networks defined by genes with transcripts belonging to different mRNA abundance classes in the small intestinal epithelial cell. The focus is the rewiring that occurs in transcription factor hubs in these networks during the differentiation of the small intestinal epithelial cell while it migrates along the crypt-villus axis and during its development from a fetal endodermal cell to a mature adult villus epithelial cell. We have generated transcriptome data for mouse small intestinal villus, crypt and fetal intestinal epithelial cells. In addition we have generated metabolome data from crypt and villus cells. Our results show that the intestinal crypt transcription factor hubs that are rewired during differentiation are involved in the cell cycle process (E2F, NF-Y) and stem cell maintenance (c-Myc). In contrast the villi are dominated by a HNF-4 villus hub, which is rewired during differentiation by the addition of network genes with relevance for lipoprotein synthesis and lipid absorption. Moreover, we have identified a villus NF-kB hub, which was revealed by comparison of the villus and endoderm transcriptomes. The rewiring of the NF-kB villus hub during intestinal development reflects transcriptional activity established by host and microflora interactions. To aid in the mining of our results we have developed a web portal (http://gastro.imbg.ku.dk/mousecv/) allowing easy linkage between the transcriptomic data, biological processes and functions. Keywords: Cell type comparison
2005-11-29 | GSE3216 | GEO
Project description:We analyzed gene expression profiles in isolated mouse LGR5+ intestinal stem cells, lineage-specific enterocyte and secretory progenitors, and terminally differentiated villus enterocytes. Gene Ontology analyses of cell type-specific transcripts indicated their expected biological functions.
2014-01-06 | GSE51398 | GEO
Project description:The mammalian liver consists of hexagonal-shaped lobules, radially polarized by blood flow and morphogens. Key liver genes have been shown to be differentially expressed along the lobule axis, a phenomenon termed zonation, but a detailed genome-wide reconstruction of this spatial division of labor has not been achieved. Here we measure the whole transcriptome of thousands of single mouse liver cells and infer their lobule coordinates using a panel of zonated landmark genes, characterized with single-molecule FISH. We obtain a genome-wide reconstruction of liver zonation profiles with unprecedented spatial resolution. We find that more than 50% of liver genes are significantly zonated and uncover abundant non-monotonic profiles that peak at the mid-lobule layers. Our approach can facilitate reconstruction of similar spatial genomic blueprints for other mammalian organs.
2016-11-29 | GSE84498 | GEO
Project description:Longitudinal zonation of epithelial cells across the mammalian small intestine defines five domains of nutrient absorption.
2023-11-28 | GSE201857 | GEO
Project description:Longitudinal zonation of epithelial cells across the mammalian small intestine defines five domains of nutrient absorption.
2023-11-28 | GSE201855 | GEO