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Terminal differentiation of villus-tip enterocytes is governed by distinct members of Tgfb superfamily

ABSTRACT: Terminal differentiation of villus-tip enterocytes is governed by distinct members of Tgfb superfamily

PROVIDER: PRJNA895015 | ENA |

REPOSITORIES: ENA

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Terminal differentiation of villus-tip enterocytes is governed by distinct members of Tgfb superfamily

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

Terminal differentiation of villus tip enterocytes is governed by distinct Tgfβ superfamily members.

Project description: Not available

| S-EPMC10481656 | biostudies-literature

Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis

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

Terminal differentiation of villus tip enterocytes is governed by distinct Tgfβ superfamily members

Project description: Not available

| S-SCDT-10_15252-EMBR_202256454 | biostudies-other

Gene expression in intestinal epithelial crypt and villus cell populations

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

Intestinal BMP SMADs impart the mid-villus pattern via direct targeting of villus zonation genes and by controlling a transcription factor hierarchy [CUT&Run]

Project description:Intestinal villus enterocytes exist in spatially restricted cell states, called zones, and continuously transdifferentiate as they migrate toward the villus tip. Bone morphogenetic protein (BMP) signaling through the BMPR1A receptor is required for zonation of enterocytes; however, the molecular mechanisms and transcriptional regulators downstream of BMP ligands/receptors are unclear. Using compound genetic mouse models and epigenomic techniques, we find that SMAD1 and SMAD5 are necessary for activation of middle villus zone genes via direct binding and control of a transcription factor hierarchy. Spatial transcriptomics reveal a homeotic-like shift in the villus pattern of SMAD1/SMAD5 double mutants, with the villus bottom and tip domains expanding at the expense of the middle. Surprisingly, SMAD1 and SMAD5 are not required for regulation of villus tip identity, which is dependent on SMAD4. Epigenomics approaches identify a mechanism for villus patterning in which SMAD1/5 directly activate some mid-villus genes and control others via a transcription factor hierarchy, including a SMAD-regulated transcription factor, TBX3, as a downstream effector of villus zonation.

2026-08-05 | GSE313354 | GEO