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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE72190 | GEO | 2016/08/19

SECONDARY ACCESSION(S): PRJNA293276

REPOSITORIES: GEO

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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

Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells

Project description:The intestinal epithelium has a remarkably high turnover in homeostasis. It remains unresolved how turnover is orchestrated at the cellular level and how the behaviour of stem and progenitor cells ensures tissue maintenance. To address this, we combined quantitative fate mapping in three complementary mouse models with mathematical modelling and single-cell RNA sequencing. Our integrated approach generated a spatially and temporally defined model of crypt maintenance that is based on two cycling populations: crypt-based columnar (CBC) and transit amplifying (TA) cells. Validation experiments substantiated the predictions from the model revealing TA cells as the major contributor to the absorptive lineage, while balanced CBC cell fate choices controlled the numbers of cells in the secretory lineage. By unravelling these mechanisms, we gain insights into the process of tissue turnover and provide direct evidence to support the notion of CBC cells as the major driver of the intestinal epithelium replenishment.

2024-12-06 | GSE241524 | GEO

CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling

Project description:Epithelial polarity is controlled by a polarity machinery including the Rho GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific deletion of CDC42 in Olfm4-IRES-eGFPCreERT2;CDC42flox/flox mice, we found that ISC-initiated CDC42 loss caused a drastic hyper-proliferation of transit amplifying (TA) cells and disrupted epithelial polarity. CDC42-null crypts displayed expanded TA cell and diminished ISC populations, accompanied by elevated hippo signaling via YAP/TAZ - Ereg and mTOR activation, independent from canonical Wnt signaling. YAP/TAZ conditional knockout restored the balance of ISC/TA cell populations and crypt proliferation but did not rescue the polarity in CDC42-null small intestine. mTOR or EGFR inhibitor treatment of CDC42 KO mice exhibited similar rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of Scribble in intestinal epithelial cells mimics that of CDC42 KO defects including crypt hyperplasia and hippo signaling activation. Mammalian epithelial polarity regulates ISC and TA cell fate and proliferation via a hippo-Ereg-mTOR cascade.

2021-10-23 | GSE166736 | GEO

Integrin αEβ7+ T cells direct intestinal stem cell fate decision via adhesive signaling

Project description:Intestinal stem cells (ISCs) maintain gut homeostasis by differentiating into different epithelial cell types, which is precisely regulated by a niche of accessory cell types. In the niche, lymphocytes may interact with stem and transient amplifying (TA) cells in the intestinal crypts. However, it is unknown whether and how the lymphocyte- stem/TA cell contacts affect ISC differentiation. Here we discover and mechanistically dissect the role of T cell-stem/TA cell contacts in ISC fate decision. We found T cells are often seen in contact with ISCs and TA cells in the small intestinal crypts, whereas B cell-stem/TA cell interaction was hardly observed. Using single-cell RNA sequencing and immunostaining, we showed that depletion of intestinal lymphocytes resulted in aberrant ISC differentiation in mice, with decreased Paneth and goblet cells, increased enteroendocrine cells and impaired enterocyte maturation. Transferring T cells but not B cells into those mice efficiently restored normal ISC differentiation. Mechanistically, integrin αEβ7 on T cells binds to E-cadherin on ISCs and TA cells. Blocking this adhesion suppressed Wnt signaling in ISCs and TA cells and promoted Notch signaling in TA cells, leading to defective ISC differentiation. In vitro study using purified αEβ7 protein showed consistent effects on the intestinal organoid differentiation. Taken together, our study reveals that the gut-resident integrin αEb7+ T cells regulate the ISC differentiation through adhesion between αEβ7 on T cells and E-cadherin on ISCs and TA cells. The αEβ7-E-cadherin adhesive signaling is critical for the fate decision of ISCs and the maintenance of intestinal homeostasis.

2022-08-02 | GSE135316 | GEO

Adiponectin regulated by IAA in Paneth cells controls renewal and differentiation of gut stem cells to maintain homeostasis of epithelial cells (small intestinal epithelium)

Project description:Crypt cells (mainly stem and transit amplifying (TA) cells) in Adipfl/flpVilli-CreT (gut epithelial cell adiponectin conditioned knockout) mice exhibited stronger ability of renewal and differentiation. ScRNA-seq found that there had much more enrichment intestinal stem and TA cells in Adipfl/flpVilli-CreT mice. The renewal and development of gut epithelial cells in irradiated or DSS (dextran sulfate sodium) treated Adipfl/flpVilli-CreT mice was faster than control Adipfl/flp mice. In vitro culture gut organoid of Adipfl/flpVilli-CreT mice exhibited faster growth than those from Adipfl/flp mice.

2024-06-21 | GSE270099 | GEO

Expression data from FACS-purified Lgr5-EGFP+ intestinal cells from Ubc9+/+ and Ubc9+/- mice

Project description:The Lgr5+ intestinal stem cell, Paneth and transit-amplifying cell compartment constitute the intestinal crypt which is the constant source of differentiated epithelial cells that replenish the intestinal villi ensuring organ maintenance and regeneration. The Lgr5+ crypt-based columnar (CBC) cells have been identified as the intestinal stem cells (ISCs) and, importantly, as cells-of-origin of intestinal cancer. We used microarrays to detail the global program of gene expression in normal ISCs describing a mild downregulation of the sumoylation (post-translational modification (PTM) of proteins by SUMO) imposed by the loss of one allele of the unique E2-conjugating enzyme (Ubc9) of the pathway.

2020-09-14 | GSE146106 | GEO

Gall&Pin2022 - ODE model of the intestinal epithelium

Project description:We developed a compartmental model of the small intestinal epithelium that describes stem and progenitor cell proliferation and differentiation and cell migration onto the villus. The model includes a negative feedback loop from villus cells to regulate crypt proliferation and integrates heterogeneous epithelial-related processes, such as the transcriptional profile, citrulline kinetics and probability of diarrhea.

2023-09-04 | MODEL2212120003 | BioModels

Gene expression profiles of Lgr5-GFP high and Lgr5-GFP low cells in small intestines of Itgb7+/+ Lgr5-GFP mice and Itgb7-/- Lgr5-GFP mice

Project description:Intestinal stem cell (ISC) differentiation is regulated precisely by a niche in the crypt, where lymphocytes may interact with stem and transient amplifying (TA) cells. However, whether and how lymphocyte-stem/TA cell contact affects ISC differentiation is largely unknown. Here, we uncover a novel role of T cell-stem/TA cell contact in ISC fate decisions. We show that intestinal lymphocyte depletion results in skewed ISC differentiation in mice, which can be rescued by T cell transfer. Mechanistically, integrin αEβ7 expressed on T cells binds to E-cadherin on ISCs and TA cells, triggering E-cadherin endocytosis and the consequent Wnt and Notch signaling alterations. Blocking αEβ7—E-cadherin adhesion suppresses Wnt signaling and promotes Notch signaling in ISCs and TA cells, leading to defective ISC differentiation. Thus, αEβ7+ T cells regulate ISC differentiation at single-cell level through cell-cell contact-mediated αEβ7—E-cadherin adhesion signaling, highlighting a critical role of the T cell-stem/TA cell contact in maintaining intestinal homeostasis.

2021-09-14 | GSE133691 | GEO

PTEN-deficient intestinal stem cells initiate intestinal polyposis

Project description:Intestinal polyposis, a precancerous neoplasia, results primarily from an abnormal increase in the number of crypts. Crypts contain intestinal stem cells (ISCs). Thus intestinal polyposis provides an ideal condition for studying stem cell involvement in polyp/tumor formation. Using a conditional knock-out mouse model, we found that the tumor suppressor Phosphatase of Tension homolog (PTEN) governs the proliferation rate and number of ISCs and loss of PTEN results in an excess of ISCs. In PTEN mutants, excess ISCs initiate de-novo crypt formation and crypt fission, recapitulating crypt production in fetal/neonatal intestine. Microarray studies were used to profile the changes in gene expression that occurred when PTEN was knocked out in the intestine. Keywords: Disease state analysis, genetic modification, Intestinal polyposis, PTEN mutant, Cowden disease mouse model

2006-11-18 | GSE6078 | GEO

FZD5 is an essential regulator of intestinal crypt homeostasis and surrogate Wnt agonist response

Project description:The rapid regeneration of the small intestinal epithelium is sustained by crypt intestinal stem cells (ISCs). Wnt/b-catenin signaling is essential for intestinal crypt homeostasis and maintenance of Lgr5+ ISC, and yet no single or combinatorial knockout of Frizzled (FZD) genes, representing Wnt receptors, has phenocopied the severe intestinal epithelial effects of Wnt signaling blockade. The elusive identification of specific Frizzled (Fzd) receptor(s) underlying homeostatic proliferation and ISC function would greatly inform therapeutic mucosal repair strategies. In prior pharmacologic studies, bioengineered antagonists that block Wnt binding to both FZD5 and FZD8 receptors induced lethal crypt and villus loss, implicating FZD5 and/or FZD8 as essential for ISCs maintenance. Here, the potential function of Fzd5 in during intestinal homeostasis was examined by epithelial-specific Fzd5 ko, which rapidly elicited lethal pan-intestinal crypt and villus loss, and by Lgr5-specific Fzd5 cKO, which strongly reduced Lgr5+ ISC while inducing their premature differentiation. In parallel, Fzd5 cKO potently repressed Wnt target gene expression, with phenotypic rescue by constitutive activation of b-catenin in vivo and confirmation upon in vitro organoid culture. Fzd5 cKO but not Fzd8 cKO in organoids ablated responsiveness to dual specificity bioengineered FZD5/FZD8-selective Wnt surrogate agonists, which reversed DSS-induced colitis phenotypes in both wild-type and Fzd8 cKO mice. Overall, our results implicate the FZD5 receptor as an essential regulator of crypt homeostasis, Lgr5+ ISCs and intestinal response to bioengineered Wnt surrogate agonists.

2024-10-18 | GSE233260 | GEO

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