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Journal ArticleDOI

Subepithelial telocytes are an important source of Wnts that supports intestinal crypts

TL;DR: Subepithelial telocytes are identified as a source of Wnt signals that enable proliferation and differentiation of intestinal stem cells, an essential function for maintenance of the intestinal epithelium.
Abstract: Tissues that undergo rapid cellular turnover, such as the mammalian haematopoietic system or the intestinal epithelium, are dependent on stem and progenitor cells that proliferate to provide differentiated cells to maintain organismal health. Stem and progenitor cells, in turn, are thought to rely on signals and growth factors provided by local niche cells to support their function and self-renewal. Several cell types have been hypothesized to provide the signals required for the proliferation and differentiation of the intestinal stem cells in intestinal crypts1-6. Here we identify subepithelial telocytes as an important source of Wnt proteins, without which intestinal stem cells cannot proliferate and support epithelial renewal. Telocytes are large but rare mesenchymal cells that are marked by expression of FOXL1 and form a subepithelial plexus that extends from the stomach to the colon. While supporting the entire epithelium, FOXL1+ telocytes compartmentalize the production of Wnt ligands and inhibitors to enable localized pathway activation. Conditional genetic ablation of porcupine (Porcn), which is required for functional maturation of all Wnt proteins, in mouse FOXL1+ telocytes causes rapid cessation of Wnt signalling to intestinal crypts, followed by loss of proliferation of stem and transit amplifying cells and impaired epithelial renewal. Thus, FOXL1+ telocytes are an important source of niche signals to intestinal stem cells.
Citations
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Journal ArticleDOI
25 Jul 2019-Cell
TL;DR: An atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals is generated, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which are associated with resistance to anti-TNF treatment.

680 citations

Journal ArticleDOI
04 Oct 2018-Cell
TL;DR: This work defines how the colonic mesenchyme remodels to fuel inflammation and barrier dysfunction in IBD.

380 citations


Cites background from "Subepithelial telocytes are an impo..."

  • ...Two recent murine studies deleted key proteins required for Wnt secretion in Foxl1- and Gli1-producing intestinal stromal cells, respectively, which led to crypt collapse and further supports S2 classification as a mesenchymal niche cell (Degirmenci et al., 2018; Shoshkes-Carmel et al., 2018)....

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Journal ArticleDOI
15 Nov 2018-Cell
TL;DR: It is shown that MHCII+ Lgr5+ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4+ T helper (Th) cells, which orchestrate tissue-wide responses to external signals.

335 citations


Cites background from "Subepithelial telocytes are an impo..."

  • ...ISC differentiation depends on external signals from both epithelial and non-epithelial cells, especially stromal cells (Degirmenci et al., 2018; Shoshkes-Carmel et al., 2018)....

    [...]

Journal ArticleDOI
24 Apr 2019-Nature
TL;DR: These findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behaviour that results in the formation of complex multicellular asymmetric structures.
Abstract: Intestinal organoids are complex three-dimensional structures that mimic the cell-type composition and tissue organization of the intestine by recapitulating the self-organizing ability of cell populations derived from a single intestinal stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical sphere differentiate into Paneth cells, which generate the stem-cell niche and lead to asymmetric structures such as the crypts and villi. Here we combine single-cell quantitative genomic and imaging approaches to characterize the development of intestinal organoids from single cells. We show that their development follows a regeneration process that is driven by transient activation of the transcriptional regulator YAP1. Cell-to-cell variability in YAP1, emerging in symmetrical spheres, initiates Notch and DLL1 activation, and drives the symmetry-breaking event and formation of the first Paneth cell. Our findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behaviour that results in the formation of complex multicellular asymmetric structures.

314 citations

Journal ArticleDOI
TL;DR: An improved understanding of CAF biology could lead to the development of novel stroma-based diagnostics, prognostics and therapeutics, and the clinical implications of CAFs as biomarkers and potential targets for prevention and treatment of patients with gastrointestinal cancer are discussed.
Abstract: The tumour microenvironment, also termed the tumour stroma or tumour mesenchyme, includes fibroblasts, immune cells, blood vessels and the extracellular matrix and substantially influences the initiation, growth and dissemination of gastrointestinal cancer. Cancer-associated fibroblasts (CAFs) are one of the critical components of the tumour mesenchyme and not only provide physical support for epithelial cells but also are key functional regulators in cancer, promoting and retarding tumorigenesis in a context-dependent manner. In this Review, we outline the emerging understanding of gastrointestinal CAFs with a particular emphasis on their origin and heterogeneity, as well as their function in cancer cell proliferation, tumour immunity, angiogenesis, extracellular matrix remodelling and drug resistance. Moreover, we discuss the clinical implications of CAFs as biomarkers and potential targets for prevention and treatment of patients with gastrointestinal cancer.

291 citations

References
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Journal ArticleDOI
TL;DR: EdgeR as mentioned in this paper is a Bioconductor software package for examining differential expression of replicated count data, which uses an overdispersed Poisson model to account for both biological and technical variability and empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference.
Abstract: Summary: It is expected that emerging digital gene expression (DGE) technologies will overtake microarray technologies in the near future for many functional genomics applications. One of the fundamental data analysis tasks, especially for gene expression studies, involves determining whether there is evidence that counts for a transcript or exon are significantly different across experimental conditions. edgeR is a Bioconductor software package for examining differential expression of replicated count data. An overdispersed Poisson model is used to account for both biological and technical variability. Empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference. The methodology can be used even with the most minimal levels of replication, provided at least one phenotype or experimental condition is replicated. The software may have other applications beyond sequencing data, such as proteome peptide count data. Availability: The package is freely available under the LGPL licence from the Bioconductor web site (http://bioconductor.org).

29,413 citations

Journal ArticleDOI
TL;DR: Using this fixative and the peroxidase-labeled antibody technique, basement membrane antigen was localized within the cisternae of endoplasmic reticulum of parietal yolk sac cells and in extracellular basement membranes with adequate tissue preservation, a task which has not been successfully accomplished by conventional fixatives.
Abstract: A new fixative which primarily stabilizes carbohydrate moieties was developed for immunoelectron microscopy. It contains periodate, lysine and paraformaldehyde. Theoretically, the carbohydrates are oxidized by periodate and cross-linked by lysine. The fixative can preserve antigenicity as well as paraformaldehyde and ultrastructure as well as glutaraldehyde. Using this fixative and the peroxidase-labeled antibody technique, basement membrane antigen was localized within the cisternae of endoplasmic reticulum of parietal yolk sac cells and in extracellular basement membranes with adequate tissue successfully accomplished by conventional

3,819 citations

Journal ArticleDOI
01 Sep 2007-Genesis
TL;DR: The mT/mG mouse as mentioned in this paper is a double-fluorescent Cre reporter mouse that expresses membrane-targeted tandem dimer tomato (mT) prior to Cre-mediated excision and membranetargeted green fluorescent protein (mG) after excision.
Abstract: The Cre/loxP system has been used extensively for conditional mutagenesis in mice. Reporters of Cre activity are important for defining the spatial and temporal extent of Cre-mediated recombination. Here we describe mT/mG, a double-fluorescent Cre reporter mouse that expresses membrane-targeted tandem dimer Tomato (mT) prior to Cre-mediated excision and membrane-targeted green fluorescent protein (mG) after excision. We show that reporter expression is nearly ubiquitous, allowing visualization of fluorescent markers in live and fixed samples of all tissues examined. We further demonstrate that mG labeling is Cre-dependent, complementary to mT at single cell resolution, and distinguishable by fluorescence-activated cell sorting. Both membrane-targeted markers outline cell morphology, highlight membrane structures, and permit visualization of fine cellular processes. In addition to serving as a global Cre reporter, the mT/mG mouse may also be used as a tool for lineage tracing, transplantation studies, and analysis of cell morphology in vivo.

2,972 citations

Journal ArticleDOI
TL;DR: In contrast to existing lacZ reporter lines, where lacZ expression cannot easily be detected in living tissue, the EYFP and ECFP reporter strains are useful for monitoring the expression of Cre and tracing the lineage of these cells and their descendants in cultured embryos or organs.
Abstract: Background Several Cre reporter strains of mice have been described, in which a lacZ gene is turned on in cells expressing Cre recombinase, as well as their daughter cells, following Cre-mediated excision of a loxP-flanked transcriptional "stop" sequence. These mice are useful for cell lineage tracing experiments as well as for monitoring the expression of Cre transgenes. The green fluorescent protein (GFP) and variants such as EYFP and ECFP offer an advantage over lacZ as a reporter, in that they can be easily visualized without recourse to the vital substrates required to visualize β-gal in living tissue.

2,941 citations

Journal ArticleDOI
20 Jan 2011-Nature
TL;DR: It is concluded that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell, in colon crypts, and co-culturing of sorted stem cells with Paneth cells markedly improves organoid formation.
Abstract: Homeostasis of self-renewing small intestinal crypts results from neutral competition between Lgr5 stem cells, which are small cycling cells located at crypt bottoms. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells that are known to produce bactericidal products such as lysozyme and cryptdins/defensins. Single Lgr5-expressing stem cells can be cultured to form long-lived, self-organizing crypt-villus organoids in the absence of non-epithelial niche cells. Here we find a close physical association of Lgr5 stem cells with Paneth cells in mice, both in vivo and in vitro. CD24(+) Paneth cells express EGF, TGF-α, Wnt3 and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells markedly improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. In colon crypts, CD24(+) cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell.

2,160 citations

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