Regulation of self-renewal and differentiation by the intestinal stem cell niche.
ABSTRACT The gastrointestinal epithelium is a highly organised tissue that is constantly being renewed. In order to maintain homeostasis, the balance between intestinal stem cell (ISC) self-renewal and differentiation must be carefully regulated. In this review, we describe how the intestinal stem cell niche provides a unique environment to regulate self-renewal and differentiation of ISCs. It has traditionally been believed that the mesenchymal myofibroblasts play an important role in the crosstalk between ISCs and the niche. However, recent evidence in Drosophila and in vertebrates suggests that epithelial cells also contribute to the niche. We discuss the multiple signalling pathways that are utilised to regulate stemness within the niche, including members of the Wnt, BMP and Hedgehog pathways, and how aberrations in these signals lead to disruption of the normal crypt-villus axis. Finally, we also discuss how CDX1 and inhibition of the Notch pathway are important in specifying enterocyte and goblet cell differentiation respectively.
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ABSTRACT: The intestinal mucosa undergoes a continual process of proliferation, differentiation and apoptosis, which is regulated by multiple signaling pathways. Previously, we have shown that the nuclear factor of activated T-cells 5 (NFAT5) is involved in the regulation of intestinal enterocyte differentiation. Here, we show that treatment with sodium chloride (NaCl), which activates NFAT5 signaling, increased mTORC1 repressor REDD1 protein expression and inhibited mTOR signaling; these alterations were attenuated by knockdown of NFAT5. Knockdown of NFAT5 activated mTOR signaling and significantly inhibited REDD1 mRNA expression and protein expression. Consistently, overexpression of NFAT5 increased REDD1 expression. In addition, knockdown of REDD1 activated mTOR and Notch signaling, whereas treatment with mTOR inhibitor rapamycin repressed Notch signaling and increased the expression of the goblet cell differentiation marker mucin2 (MUC2). Moreover, knockdown of NFAT5 activated Notch signaling and decreased MUC2 expression, while overexpression of NFAT5 inhibited Notch signaling and increased MUC2 expression. Our results demonstrate a role for NFAT5 in the regulation of mTOR signaling in intestinal cells. Importantly, these data suggest that NFAT5 participates in the regulation of intestinal homeostasis via the suppression of mTORC1/Notch signaling pathway.Molecular Biology of the Cell 07/2014; · 4.55 Impact Factor
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ABSTRACT: Stem cells are the developmentally early forms of flexible cell types which can give rise to multiple cell types. Embryonic and adult stem cells are the two types of stem cells occurring in the mammalian system, which are responsible for giving rise to myriads of cell types during the development. Accordingly, harnessing the potential of stem cells is considered to have great significance for therapeutic purpose. Also, stem cells have certain features like unlimited proliferation potential, which they share closely, with the rogue cells of any mammalian system, which are cancer cells. In addition, there are stem cells, which give rise to cancer and are called cancer stem cells. In this review, we have addressed the developmental aspects of stem cells, cancer cells and cancer stem cells, their respective biological functions in maintaining an intricate balance to decide their respective contributions to the usefulness or harmfulness in the biological system.Journal of Stem Cell Research & Therapy. 02/2014; 4:173.
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ABSTRACT: Intestinal inflammation is widely recognized as a pivotal player in health and disease. Defined cytologically as the infiltration of leukocytes in the lamina propria layer of the intestine, it can damage the epithelium and, on a chronic basis, induce inflammatory bowel disease and potentially cancer. The current view thus dictates that blood cell infiltration is the instigator of intestinal inflammation and tumor-promoting inflammation. This is based partially on work in humans and mice showing that intestinal damage during microbially mediated inflammation activates phagocytic cells and lymphocytes that secrete inflammatory signals promoting tissue damage and tumorigenesis. Nevertheless, extensive parallel work in the Drosophila midgut shows that intestinal epithelium damage induces inflammatory signals and growth factors acting mainly in a paracrine manner to induce intestinal stem cell proliferation and tumor formation when genetically predisposed. This is accomplished without any apparent need to involve Drosophila hemocytes. Therefore, recent work on Drosophila host defense to infection by expanding its main focus on systemic immunity signaling pathways to include the study of organ homeostasis in health and disease shapes a new notion that epithelially emanating cytokines and growth factors can directly act on the intestinal stem cell niche to promote "regenerative inflammation" and potentially cancer.Pathogens (Basel, Switzerland). 01/2013; 2(2):209-231.