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Single-Cell Transcriptomes of the Regenerating Intestine Reveal a Revival Stem Cell [part 2]

ABSTRACT: The weekly turnover of the intestinal epithelium is driven by multipotent, Lgr5+, crypt base columnar cells (CBCs). In response to injury, however, Lgr5+ cells are lost but then re-emerge and are required for successful recovery. How these resurgent Lgr5+ stem cells arise is unclear. We transcriptionally profiled single cells from regenerating intestinal epithelia and identified a unique cell type we term the revival stem cell (rSC). rSCs are mutually exclusive to CBCs and are distinguished by elevated expression of cell survival and DNA repair genes. In homeostasis, rSCs are extremely rare, but nevertheless give rise to all the major cell types of the intestine including crypt-villus axes. After damage rSCs display a 20-fold, Yap-dependent, transient expansion, reconstitute the Lgr5+ CBC compartment and are required to regenerate a functional intestine. These studies define a unique stem cell phenotype that is mobilized by damage to reconstitute the intestinal epithelium.

ORGANISM(S): Mus musculus

PROVIDER: GSE123515 | GEO | 2019/02/28

REPOSITORIES: GEO

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Single-Cell Transcriptomes of the Regenerating Intestine Reveal a Revival Stem Cell [part 1]

Project description:The weekly turnover of the intestinal epithelium is driven by multipotent, Lgr5+, crypt base columnar cells (CBCs). In response to injury, however, Lgr5+ cells are lost but then re-emerge and are required for successful recovery. How these resurgent Lgr5+ stem cells arise is unclear. We transcriptionally profiled single cells from regenerating intestinal epithelia and identified a unique cell type we term the revival stem cell (rSC). rSCs are mutually exclusive to CBCs and are distinguished by elevated expression of cell survival and DNA repair genes. In homeostasis, rSCs are extremely rare, but nevertheless give rise to all the major cell types of the intestine including crypt-villus axes. After damage rSCs display a 20-fold, Yap-dependent, transient expansion, reconstitute the Lgr5+ CBC compartment and are required to regenerate a functional intestine. These studies define a unique stem cell phenotype that is mobilized by damage to reconstitute the intestinal epithelium.

2019-02-28 | GSE117783 | GEO

Transcription profiling of mouse intestinal cells expressing Lgr5 at high or low levels or with Ascl2 conditionally knocked out shows Ascl2 controls intestinal stem cell fate

Project description:The small intestinal epithelium is the most rapidly self-renewing tissue of mammals. Proliferative cells are confined to crypts, while differentiated cell types predominantly occupy the villi. We recently demonstrated the existence of a long-lived pool of cycling stem cells defined by Lgr5 expression and intermingled with post-mitotic Paneth cells at crypt bottoms. We have now determined a gene signature for these so called Crypt Base Columnar (CBC) cells. One of the genes within this stem cell signature is the Wnt target Ascl2. Transgenic expression of the Ascl2 transcription factor throughout the intestinal epithelium induces crypt hyperplasia and de novo crypt formation on villi. Induced deletion of the Ascl2 gene in adult small intestine leads to disappearance of the CBC stem cells within days. The combined results from these gain- and loss-of-function experiments imply that Ascl2 controls intestinal stem cell fate. Experiment Overall Design: For the stem cell signature we used cell fractions of intestines from Lgr5-EGFP-ires-CreERT2 mice, expressing GFP under the control of the Lgr5 promoter. RNA was isolated from two FACS sorted cell populations, one expressing GFP at high levels (GFPhi) and the other expressing GFP at low levels (GFPlo). For the analysis of Ascl2 target genes RNA was isolated from intestinal epithelial cells of Ah-Cre/Ascl2floxed/floxed animals and Ah-Cre/Ascl2floxed/wt control animals 3 and 5 days post induction. Differentially labelled cRNA from GFPhi and GFPlo cells from two different sorts (each combining three different mice) were hybridised on 4X44K Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in two dye swap experiments, resulting in four individual arrays. For the Ascl2 target gene analysis we analyzed the 3 and 5 days PI experiments in two dye swap experiments, resulting in four individual arrays.

2009-03-25 | E-GEOD-14201 | biostudies-arrayexpress

Transcription factor Achaete scute-like 2 (Ascl2) controls intestinal stem cell fate

2009-03-13 | GSE14201 | GEO

Single cell profiling of SW480 subtype-specific subcutaneous and orthotopic xenografts (SW480-CBC and SW480-RSC) as presented in "Colorectal Cancer Stem Cell Subtypes Orchestrate Distinct Tumor Microenvironments" [scRNA-seq]

Project description:Tumor heterogeneity derives from diverse populations of cancer cells that contribute unique properties to the microenvironment and tumor progression. While multiple classification systems have been developed to define tumor subtypes in colorectal cancer (CRC), the lack of single cell resolution has prohibited a better understanding of how these distinct cancer cell subtypes influence the overall tumor phenotype. Here were report that two cancer stem cell subtypes that are oncogenic versions of the intestinal Crypt Base Columnar (CBC) and Regenerative Stem Cell (RSC) populations, are commonly co-present in human CRC. We develop subtype-specific xenograft models utilizing a heterogeneous patient cell line (SW480) that contains CBCs and RSCs, and we define their tumor microenvironments at high resolution via single cell RNA sequencing. RSCs create differentiated, inflammatory, slow growing tumors. CBCs create proliferative, immune-suppressive, invasive tumors. With this enhanced resolution, we unify current CRC patient classification schema with TME phenotypes and organization.

2024-04-25 | GSE254890 | GEO

Deep transcriptional profiling of the two cancer stem cell populations present in the SW480 cell line as presented in "Colorectal Cancer Stem Cell Subtypes Orchestrate Distinct Tumor Microenvironments" [bulk RNA-seq]

2024-04-25 | GSE254891 | GEO

Single intestinal stem cells build crypt-villus structures in vitro without a cellular niche

2009-04-03 | GSE14594 | GEO

ZIP7 is indispensable for proliferation of intestinal epithelial cells and maintenance of intestinal stem cells

Project description:Intestinal epithelium are generated by intestinal stem cells, which are recognized morphologically as slender columnar cells at the base of the crypt. Stem cells produce transit-amplifying (TA) cells, which divide a number of times and the daughter cells differentiate into absorptive enterocytes as well as secretory-lineages. Intestinal stem cells highly express Lgr5 which is decreased in TA cells. Here, we show that the zinc transported SLC39A7/ZIP7 is essential for the proliferation of TA cells and maintenance of intestinal stem cells. Lgr5Med TA cells derived from Zip7-deficient mice upregulated the expression of unfold protein responses-related genes including pro-apoptotic genes, indicating of induction of ER stress in these cells. The same effect was seen in Lgr5Hi stem cells derived from Zip7-deficient mice. We conclude that ZIP7 is fundamental to the maintenance of crypt homeostasis by resolving ER stress. Small intestinal crypts were isolated form tamoxifen-treated control (Zip7flox/+, Villin-CreERT2, Lgr5-EGFP-ires-CreERT2) and tamoxifen-treated Zip7â??IEC (Zip7flox/flox, Villin-CreERT2, Lgr5-EGFP-ires-CreERT2) mice. We FACS purified intestinal crypt cells according to their Lgr5 expression levels. RNA was isolated from four FACS sorted cell populations: Lgr5Hi cells and Lgr5Med cells derived from control mice, Lgr5Hi cells and Lgr5Med cells derived from Zip7â??IEC mice. Isolated RNA was analyzed using the Affymetrix platform.

2016-08-19 | E-GEOD-72190 | biostudies-arrayexpress

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Project description:The currently accepted intestinal epithelial cell organization model equates crypt base columnar (CBC) cells, marked by high levels of Lgr5 expression, with the intestinal stem cell (ISC). However, recent intestinal regeneration studies have uncovered limitations of the ‘Lgr5-CBC’ model, leading to two major views: one favoring the presence of a quiescent reserve stem cell population, the other calling for differentiated cell plasticity. To test if an alternative model may help reconcile these perspectives, we studied the hierarchical organization of crypt epithelial cells in an unbiased fashion, by combining high-resolution, single-cell profiling and lineage tracing in multiple transgenic mouse models. These show that Lgr5 is not a specific ISC marker; rather, cells located in the crypt isthmus, which include Lgr5low cells, comprise the ISCs that sustain tissue homeostasis. Following irradiation or intestinal injury, surviving ISCs and progenitors, but not differentiated cells, participate in intestinal regeneration, suggesting that neither de-differentiation nor reserve stem cell populations are drivers of intestinal regeneration. Our results provide a novel viewpoint for the intestinal crypt epithelium, in which ISCs localize to the crypt isthmus, and ISC potential is restricted to stem and progenitor cells.

2024-03-24 | GSE205229 | GEO

Single intestinal stem cells build crypt-villus structures in vitro without a cellular niche

Project description:The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of approximately six cycling Lgr5+ stem cells at the bottoms of small intestinal crypts1. We have now established long-term culture conditions under which single crypts undergo multiple crypt fission events, whilst simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5+ stem cells can also initiate these crypt-villus organoids. Tracing experiments indicate that the Lgr5+ stem cell hierarchy is maintained in organoids. We conclude that intestinal crypt-villus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche. Keywords: expression profiling Freshly isolated small intestinal crypts from two mice were divided into two parts. RNA was directly isolated from one part (RNeasy Mini Kit, Qiagen), the other part was cultured for one week according to the conditions described in the associated paper, followed by RNA isolation. We prepared labeled cRNA following the manufacturer’s instruction (Agilent Technologies). Differentially labelled cRNA from small intestinal crypts and organoids were hybridised separately for the two mice on a 4X44k Agilent Whole Mouse Genome dual colour Microarrays (G4122F) in two dye swap experiments, resulting in four individual arrays.

2009-04-03 | E-GEOD-14594 | biostudies-arrayexpress

Reg4+ Deep Crypt Secretory cells function as epithelial niche for Lgr5+ stem cells in colon

Project description:Lgr5+ stem cells reside at crypt bottoms of the small and large intestine. Small intestinal Paneth cells supply Wnt3, EGF and Notch signals to neighboring Lgr5+ stem cells. While the colon lacks Paneth cells, Deep Crypt Secretory (DCS) cells are intermingled with Lgr5+ stem cells at crypt bottoms. Here, we report Reg4 as a marker of DCS cells. To investigate a niche function, we eliminated DCS cells using the diphtheria-toxin receptor gene knocked into the murine Reg4 locus. Ablation of DCS cells results in loss of stem cells from colonic crypts and disrupts gut homeostasis and colon mini-gut formation. In agreement, sorted Reg4+ DCS cells promote organoid formation of single Lgr5+ colon stem cells. Stem cells are forced to generate DCS cells in vitro by combined Notch inhibition and Wnt activation. We conclude that Reg4+ DCS cells serve as Paneth cell equivalents in the colon crypt niche.

2016-10-05 | GSE63256 | GEO

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