Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis
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ABSTRACT:
PROVIDER: PRJNA430822 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11131077_1.fastq.gz | Fastqsanger.gz | |||
| SRR11131077_2.fastq.gz | Fastqsanger.gz | |||
| SRR11131078_1.fastq.gz | Fastqsanger.gz | |||
| SRR11131078_2.fastq.gz | Fastqsanger.gz | |||
| SRR6502570_1.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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