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Transcriptomes of adult sorted Epcam+ CD44- enterocytes from small intestine of wildtype and CmafLEC-KO mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE189852 | GEO | 2022/08/18

REPOSITORIES: GEO

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Project description:The small intestinal epithelium mediates vital functions of nutrient absorption and host defense. The spatial organization of the epithelial cells along the crypt-villus axis segregates them into regions of specialized function. However, many of the mechanisms governing intestinal epithelial cell migration and the coordination of interactions with adjacent cells and the extracellular matrix are not fully understood. We have evaluated in vivo gene expression patterns of ileal epithelial cells in healthy human subjects, isolated by laser capture microdissection from either the villus epithelial or crypt cell regions of the small intestinal mucosa. Expression profiles in villus epithelium and Paneth cell lineages were determined by quantitative real-time PCR, DNA microarray, and immunohistochemistry based methods. Relative expression levels of selected epithelial biomarkers were compared between the ileum, jejunum, duodenum, colon, stomach, and esophagus. Previously established biomarkers as well as a novel and distinct set of genes believed to be linked to epithelial cell motility, adhesion, and differentiation were found to be enriched in each of the two corresponding cell populations. Additionally, high baseline expression levels of innate antimicrobials, alpha defensin 5 (HD5) and regenerating islet-derived 3 alpha (Reg3A), were detected exclusively within the small bowel, most notably in the ileum, in comparison to other sites along the gastrointestinal tract. Our findings provide new and important insights regarding the molecular machinery employed by small intestinal epithelial cells to mediate their function and spatial organization in vivo. Experiment Overall Design: Surgical specimens of human intestinal mucosa were obtained from 4 individuals undergoing surgery for colon cancer, bowel obstruction, or other non-inflammatory conditions. The samples were fixed overnight in 4% (w/v) paraformaldehyde, dehydrated in a graded alcohol series and paraffin-embedded. At least 500 epithelial cells from the crypt or upper villus regions were then captured by LCMD from unstained 6Âµm thick sections using a PALM MicroLaser System Total RNA was extracted for microarray-based gene expression analysis.

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Transcriptomes of adult sorted Epcam+ CD44- enterocytes from small intestine of wildtype and CmafLEC-KO mice

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